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1.	Borhade, Sanjay R., et al. (author) Preclinical Characterization of Acyl Sulfonimidamides : Potential Carboxylic Acid Bioisosteres with Tunable Properties 2015 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 10:3, s. 455-460 Journal article (peer-reviewed)abstract Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pK(a), lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9-7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.
2.	Bozzola, Tiago, et al. (author) Sialic Acid 4-N-Piperazine and Piperidine Derivatives Bind with High Affinity to the P. mirabilis Sialic Acid Sodium Solute Symporter 2022 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 17:23 Journal article (peer-reviewed)abstract In search for novel antibacterial compounds, bacterial sialic acid uptake inhibition represents a promising strategy. Sialic acid plays a critical role for growth and colonisation of several pathogenic bacteria, and its uptake inhibition in bacteria was recently demonstrated to be a viable strategy by targeting the SiaT sodium solute symporters from Proteus mirabilis and Staphylococcus aureus. Here we report the design, synthesis and evaluation of potential sialic acid uptake inhibitors bearing 4-N-piperidine and piperazine moieties. The 4-N-derivatives were obtained via 4-N-functionalization with piperidine and piperazine nucleophiles in an efficient direct substitution of the 4-O-acetate of Neu5Ac. Evaluation for binding to bacterial transport proteins with nanoDSF and ITC revealed compounds possessing nanomolar affinity for the P. mirabilis SiaT symporter. Computational analyses indicate the engagement of a previously untargeted portion of the binding site.
3.	Briggner, Lars-Erik, et al. (author) In Silico Solid State Perturbation for Solubility Improvement 2014 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 9:4, s. 724-726 Journal article (peer-reviewed)abstract Solubility is a frequently recurring issue within pharmaceutical industry, and new methods to proactively resolve this are of fundamental importance. Here, a novel methodology is reported for intrinsic solubility improvement, using insilico prediction of crystal structures, by perturbing key interactions in the crystalline solid state. The methodology was evaluated with a set of benzodiazepine molecules, using the two-dimensional molecular structure as the only a priori input. The overall trend in intrinsic solubility was correctly predicted for the entire set of benzodiazepines molecules. The results also indicate that, in drug compound series where the melting point is relatively high (i.e., brick dust compounds), the reported methodology should be very suitable for identifying strategically important molecular substitutions to improve solubility. As such, this approach could be a useful predictive tool for rational compound design in the early stages of drug development.
4.	Di, Li, et al. (author) The Critical Role of Passive Permeability in Designing Successful Drugs 2020 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 15:20, s. 1862-1874 Research review (peer-reviewed)abstract Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.
5.	Diaz-Holguin, Alejandro, et al. (author) When Two Become One : Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists 2023 In: ChemMedChem. - : John Wiley & Sons. - 1860-7179 .- 1860-7187. ; 18:4 Journal article (peer-reviewed)abstract Farnesoid X receptor (FXR) is a nuclear receptor with an essential role in regulating bile acid synthesis and cholesterol homeostasis. FXR activation by agonists is explained by an alpha AF-2-trapping mechanism; however, antagonism mechanisms are diverse. We discuss microsecond molecular dynamics (MD) simulations investigating our recently reported FXR antagonists 2a and 2 h. We study the antagonist-induced conformational changes in the FXR ligand-binding domain, when compared to the synthetic (GW4064) or steroidal (chenodeoxycholic acid, CDCA) FXR agonists in the FXR monomer or FXR/RXR heterodimer r, and in the presence and absence of the coactivator. Our MD data suggest ligand-specific influence on conformations of different FXR-LBD regions, including the alpha 5/alpha 6 region, alpha AF-2, and alpha 9-11. Changes in the heterodimerization interface induced by antagonists seem to be associated with alpha AF-2 destabilization, which prevents both co-activator and co-repressor recruitment. Our results provide new insights into the conformational behaviour of FXR, suggesting that FXR antagonism/agonism shift requires a deeper assessment than originally proposed by crystal structures.
6.	Erdelyi, Mate, 1975, et al. (author) The Binding Mode of Side Chain- and C3-Modified Epothilones to Tubulin 2010 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 5:6, s. 911-920 Journal article (peer-reviewed)abstract The tubulin-binding mode of C3- and C15-modified analogues of epothilone A (Epo A) was determined by NMR spectroscopy and computational methods and compared with the existing structural models of tubulin-bound natural Epo A. Only minor differences were observed in the conformation of the macrocycle between Epo A and the C3-modified analogues investigated. In particular, 3-deoxy- (compound 2) and 3-deoxy-2,3-didehydro-Epo A (3) were found to adopt similar conformations in the tubulin-binding cleft as Epo A, thus indicating that the 3-OH group is not essential for epothilones to assume their bioactive conformation. None of the available models of the tubulin-epothilone complex is able to fully recapitulate the differences in tubulin-polymerizing activity and microtubule-binding affinity between C20-modified epothilones 6 (C20-propyl), 7 (C20-butyl), and 8 (C20-hydroxypropyl). Based on the results of transferred NOE experiments in the presence of tubulin, the isomeric C15 quinoline-based Epo B analogues 4 and 5 show very similar orientations of the side chain, irrespective of the position of the nitrogen atom in the quinoline ring. The quinoline side chain stacks on the imidazole moiety of -His227 with equal efficiency in both cases, thus suggesting that the aromatic side chain moiety in epothilones contributes to tubulin binding through strong van der Waals interactions with the protein rather than hydrogen bonding involving the heteroaromatic nitrogen atom. These conclusions are in line with existing tubulin polymerization and microtubule-binding data for 4, 5, and Epo B.
7.	Favalli, N, et al. (author) A DNA-Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition 2018 In: ChemMedChem. - : Wiley. - 1860-7187 .- 1860-7179. ; 13:13, s. 1303-1307 Journal article (peer-reviewed)
8.	Friedman, Ran, et al. (author) Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring 2009 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 4:8, s. 1317-1326 Journal article (peer-reviewed)abstract Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are therefore promising targets for developing drugs against malaria. We have discovered six inhibitors of PM II by high-throughput fragment-based docking of a diversity set of ∼40 000 molecules, and consensus scoring with force field energy functions. Using the common scaffold of the three most active inhibitors (IC50=2–5 μM), another seven inhibitors were identified by substructure search. Furthermore, these 13 inhibitors belong to at least three different classes of compounds. The in silico approach was very effective since a total of 13 active compounds were discovered by testing only 59 molecules in an enzymatic assay. This hit rate is about one to two orders of magnitude higher than those reported for medium- and high-throughput screening techniques in vitro. Interestingly, one of the inhibitors identified by docking was halofantrine, an antimalarial drug of unknown mechanism. Explicit water molecular dynamics simulations were used to discriminate between two putative binding modes of halofantrine in PM II.
9.	Fritzson, Ingela, et al. (author) Inhibition of Human DHODH by 4-Hydroxycoumarins, Fenamic Acids, and N-(Alkylcarbonyl)anthranilic Acids Identified by Structure-Guided Fragment Selection 2010 In: ChemMedChem. - : Wiley. - 1860-7187 .- 1860-7179. ; 5:4, s. 608-617 Journal article (peer-reviewed)abstract A strategy that combines virtual screening and structureguided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids. Structure-guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure–activity relationships upon expansion. The novel N-(alkylcarbonyl anthranilic acid class shows the most promising potency against human DHODH, with IC50 values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented.
10.	Gabel, Detlef, et al. (author) The Anionic Boron Cluster (B(12)H(11)SH)(2-) as a Means To Trigger Release of Liposome Contents. 2007 In: ChemMedChed. - : Wiley. - 1860-7179. ; 2:1, s. 51-53 Journal article (peer-reviewed)abstract Triggered release. Liposomes are novel carriers for pharmaceutical agents and can be triggered to release their contents by the addition of B12H11SH, a compound in clinical use. As systemic toxicity is decreased relative to the free drug, liposomal drugs can therefore be administered in higher concentrations before dose-limiting side effects are met. Thus, liposome-encapsulated drugs may be of great value in the therapy of diseases.
11.	Gaugaz, Fabienne Z, et al. (author) The impact of cyclopropane configuration on the biological activity of cyclopropyl-epothilones 2014 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 9:10, s. 2227-2232 Journal article (peer-reviewed)abstract Two cis-12,13-cyclopropyl-epothilone B variants have been synthesized, differing only in the configuration of the stereocenters at C12 and C13. The syntheses were based on a common allylic alcohol intermediate that was converted into the corresponding diastereomeric hydroxymethyl-cyclopropanes by means of stereoselective Charette cyclopropanations. Macrocyclizations were accomplished through ring-closing metathesis (RCM). Substantial differences between the two compounds were found with regard to microtubule binding affinity, antiproliferative activity and their effects on the cellular microtubule network. While the analogue with the cyclopropane moiety oriented in a corresponding way to the epoxide configuration in natural epothilones was almost equipotent with epothilone A, the other was significantly less active. Based on these findings, natural epothilone-like activity of cis-fused 12,13-cyclopropyl-epothilone analogues is tightly linked to the natural orientation of the cyclopropane moiety.
12.	Girardi, Benedetta, et al. (author) Selective Monovalent Galectin-8 Ligands Based on 3-Lactoylgalactoside 2022 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 17:3 Journal article (peer-reviewed)abstract Galectin-8 has gained attention as a potential new pharmacological target for the treatment of various diseases, including cancer, inflammation, and disorders associated with bone mass reduction. To that end, new molecular probes are needed in order to better understand its role and its functions. Herein we aimed to improve the affinity and target selectivity of a recently published galectin-8 ligand, 3-O-[1-carboxyethyl]-β-d-galactopyranoside, by introducing modifications at positions 1 and 3 of the galactose. Affinity data measured by fluorescence polarization show that the most potent compound reached a KD of 12 μM. Furthermore, reasonable selectivity versus other galectins was achieved, making the highlighted compound a promising lead for the development of new selective and potent ligands for galectin-8 as molecular probes to examine the protein's role in cell-based and in vivo studies.
13.	Hardes, K, et al. (author) Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin 2017 In: ChemMedChem. - : Wiley. - 1860-7187 .- 1860-7179. ; 12:8, s. 613-620 Journal article (peer-reviewed)
14.	Hartmann, Rafael, et al. (author) Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing. 2020 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 15:24, s. 2500-2512 Journal article (peer-reviewed)abstract Auristatins are a class of ultrapotent microtubule inhibitors, whose growing clinical popularity in oncology is based upon their use as payloads in antibody-drug conjugates (ADCs). The most widely utilized auristatin, MMAE, has however been shown to cause apoptosis in non-pathological cells proximal to the tumour ("bystander killing"). Herein, we introduce azastatins, a new class of auristatin derivatives encompassing a side chain amine for antibody conjugation. The synthesis of Cbz-azastatin methyl ester, which included the C2-elongation and diastereoselective reduction of two proteinogenic amino acids as key transformations, was accomplished in 22 steps and 0.76 % overall yield. While Cbz-protected azastatin methyl ester (0.13-3.0 nM) inhibited proliferation more potently than MMAE (0.47-6.5 nM), removal of the Cbz-group yielded dramatically increased IC50 -values (9.8-170 nM). We attribute the reduced apparent cytotoxicity of the deprotected azastatin methyl esters to a lack of membrane permeability. These results clearly establish the azastatins as a novel class of cytotoxic payloads ideally suited for use in next-generation ADC development.
15.	Honarparvar, Bahareh, et al. (author) Pentacycloundecane-diol-Based HIV-1 Protease Inhibitors : Biological Screening, 2D NMR, and Molecular Simulation Studies 2012 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:6, s. 1009-1019 Journal article (peer-reviewed)abstract Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compounds are reported herein, three of which displayed IC50 values in the 0.50.6 mu M range. The cytotoxicity of PCU cage peptides toward human MT-4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through-space 1H,1H distances/contacts in the EASY-ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU-based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases.
16.	Horvath, Dragos, et al. (author) Design of a general-purpose European compound screening library for EU-OPENSCREEN 2014 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 9:10, s. 2309-2326 Journal article (peer-reviewed)abstract This work describes a collaborative effort to define and apply a protocol for the rational selection of a general-purpose screening library, to be used by the screening platforms affiliated with the EU-OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening-compliant physicochemical properties, loose compliance to drug-likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre-filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in-house methodology and expertise. An in-depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics-driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general-purpose self-organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU-OPENSCREEN library could be directly compared with distributions of known bioactives of various classes. This mapping highlights the relevance of the selection and shows how the consensus reached by merging the five different 40K selections contributes to achieve this relevance. The approach also allows one to readily identify subsets of target-or target-class-oriented compounds from the EU-OPENSCREEN library to suit the needs of the diverse range of potential users. The final EU-OPENSCREEN library, assembled by merging five independent selections of 40K compounds from various expert groups, represents an excellent example of a Europe-wide collaborative effort toward the common objective of building best-in-class European open screening platforms.
17.	Kumar, Rohit, et al. (author) Structure and Energetics of Ligand–Fluorine Interactions with Galectin-3 Backbone and Side-Chain Amides : Insight into Solvation Effects and Multipolar Interactions 2019 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 14:16, s. 1528-1536 Journal article (peer-reviewed)abstract Multipolar fluorine–amide interactions with backbone and side-chain amides have been described as important for protein–ligand interactions and have been used to improve the potency of synthetic inhibitors. In this study, fluorine interactions within a well-defined binding pocket on galectin-3 were investigated systematically using phenyltriazolyl-thiogalactosides fluorinated singly or multiply at various positions on the phenyl ring. X-ray structures of the C-terminal domain of galectin-3 in complex with eight of these ligands revealed potential orthogonal fluorine–amide interactions with backbone amides and one with a side-chain amide. The two interactions involving main-chain amides seem to have a strong influence on affinity as determined by fluorescence anisotropy. In contrast, the interaction with the side-chain amide did not influence affinity. Quantum mechanics calculations were used to analyze the relative contributions of these interactions to the binding energies. No clear correlation could be found between the relative energies of the fluorine–main-chain amide interactions and the overall binding energy. Instead, dispersion and desolvation effects play a larger role. The results confirm that the contribution of fluorine–amide interactions to protein–ligand interactions cannot simply be predicted, on geometrical considerations alone, but require careful consideration of the energetic components.
18.	Malo, Marcus, et al. (author) Investigation of D1 receptor-agonist interactions and D1/D2 agonist selectivity using a combination of pharmacophore and receptor homology modelling 2012 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:3, s. 483-494 Journal article (peer-reviewed)abstract The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D1 receptor agonism and D1/D2 agonist selectivity. A 3D structure model of the D1 receptor in its agonist-bound state was constructed with a full D1 agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D1 agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor-based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D1 and D2 receptors revealed differences in shape and ligand-interacting features that determine selectivity of D1 and D2 receptor agonists. A hydrogen bond pharmacophoric feature (Ser-TM5) was shown to contribute most to the selectivity. Non-conserved residues in the binding pocket that strongly contribute to D1/D2 receptor agonist selectivity were also identified; those were Ser/Cys3.36, Tyr/Phe5.38, Ser/Tyr5.41, and Asn/His6.55 in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D1 and D2 agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand–protein interactions for which experimental information is limited.
19.	Malo, Marcus, et al. (author) Investigation of D2 receptor-agonist interactions using a combination of pharmacophore and receptor homology modelling 2012 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:3, s. 471-482 Journal article (peer-reviewed)
20.	Malo, Marcus, et al. (author) Selective pharmacophore models of dopamine D(1) and D(2) full agonists based on extended pharmacophore features. 2010 In: ChemMedChem. - : Wiley. - 1860-7187 .- 1860-7179. ; 5:2, s. 232-46 Journal article (peer-reviewed)abstract This study is focused on the identification of structural features that determine the selectivity of dopamine receptor agonists toward D(1) and D(2) receptors. Selective pharmacophore models were developed for both receptors. The models were built by using projected pharmacophoric features that represent the main agonist interaction sites in the receptor (the Ser residues in TM5 and the Asp in TM3), a directional aromatic feature in the ligand, a feature with large positional tolerance representing the positively charged nitrogen in the ligand, and sets of excluded volumes reflecting the shapes of the receptors. The sets of D(1) and D(2) ligands used for modeling were carefully selected from published sources and consist of structurally diverse, conformationally rigid full agonists as active ligands together with structurally related inactives. The robustness of the models in discriminating actives from inactives was tested against four ensembles of conformations generated by using different established methods and different force fields. The reasons for the selectivity can be attributed to both geometrical differences in the arrangement of the features, e.g., different tilt angels of the pi system, as well as shape differences covered by the different sets of excluded volumes. This work provides useful information for the design of new D(1) and D(2) agonists and also for comparative homology modeling of D(1) and D(2) receptors. The approach is general and could therefore be applied to other ligand-protein interactions for which no experimental protein structure is available.
21.	Norinder, Ulf, et al. (author) Prediction of ADMET Properties 2006 In: ChemMedChem. - : Wiley-VCH. - 1860-7179 .- 1860-7187. ; 1:9, s. 920-937 Research review (peer-reviewed)abstract This Review describes some of the approaches and techniques used today to derive in silico models for the prediction of ADMET properties. The article also discusses some of the fundamental requirements for deriving statistically sound and predictive ADMET relationships as well as some of the pitfalls and problems encountered during these investigations. It is the intension of the authors to make the reader aware of some of the challenges involved in deriving useful in silico ADMET models for drug development.
22.	Odell, Luke R, et al. (author) Azido and diazarinyl analogues of bis-tyrphostin as asymmetrical inhibitors of dynamin GTPase 2009 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 4:7, s. 1182-1188 Journal article (peer-reviewed)abstract Probing the dynamin binding site: Bis-tyrphostin (1, Bis-T), is a potent inhibitor of the phospholipid-stimulated GTPase activity of dynamin I. Analogues of Bis-T have significant potential as a biological probes for the dissection of endocytic pathways. Bis-T-derived compounds were synthesised and evaluated for their ability to inhibit the GTPase activity of dynamin I. Two analogues (23 and 24) represent the first asymmetrically substituted Bis-T analogues to retain dynamin inhibition.Two azidobenzyl amide (4 and 23) and one 3-trifluoromethyl-3H-diazirin-3-ylphenyl (24) analogues of bis-tyrphostin (1, Bis-T) were synthesised as potential photoaffinity labels for the elucidation of the binding site of compound 1 in dynamin I. Of the two azidobenzyl amide analogues (4 and 23), the terminally substituted 23 retained dynamin I GTPase inhibition (IC(50)=6.4+/-2.8 microM) whilst 4, which was substituted on the central carbon of the amide linker, displayed no activity. Analogue 24 also retained inhibitory activity (IC(50)=36+/-9 microM). Photoaffinity labelling experiments did not unequivocally elucidate the binding pocket of compound 1. However, compounds 23 and 24 represent the first asymmetrically substituted Bis-T analogues to retain dynamin inhibitory activity, providing a new direction for analogue synthesis.
23.	Odell, Luke R., et al. (author) Prodrugs of the Archetypal Dynamin Inhibitor Bis-T-22 2022 In: ChemMedChem. - : John Wiley & Sons. - 1860-7179 .- 1860-7187. ; 17:24 Journal article (peer-reviewed)abstract The Bis-T series of compounds comprise some of the most potent inhibitors of dynamin GTPase activity yet reported, e. g., (2E,2 ' E)-N,N '-(propane-1,3-diyl)bis(2-cyano-3-(3,4-dihydroxyphenyl)acrylamide) (2), Bis-T-22. The catechol moieties are believed to limit cell permeability, rendering these compounds largely inactive in cells. To solve this problem, a prodrug strategy was envisaged and eight ester analogues were synthesised. The shortest and bulkiest esters (acetate and butyl/tert-butyl) were found to be insoluble under physiological conditions, whilst the remaining five were soluble and stable under these conditions. These five were analysed for plasma stability and half-lives ranged from similar to 2.3 min (propionic ester 4), increasing with size and bulk, to greater than 24 hr (dimethyl carbamate 10). Similar profiles where observed with the rate of formation of Bis-T-22 with half-lives ranging from similar to 25 mins (propionic ester 4). Propionic ester 4 was chosen to undergo further testing and was found to inhibit endocytosis in a dose-dependent manner with IC50 similar to 8 mu M, suggesting this compound is able to effectively cross the cell membrane where it is rapidly hydrolysed to the desired Bis-T-22 parent compound.
24.	Odell, Luke R., et al. (author) Pyrimidyn‐Based Dynamin Inhibitors as Novel Cytotoxic Agents 2022 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 17:1 Journal article (peer-reviewed)
25.	Scaletti, Emma Rose, et al. (author) The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform-Selective Inhibitors 2022 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 17:18 Journal article (peer-reviewed)abstract Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial 1-carbon metabolism enzyme, which is an attractive anticancer drug target as it is highly upregulated in cancer but is not expressed in healthy adult cells. Selective MTHFD2 inhibitors could therefore offer reduced side-effects during treatment, which are common with antifolate drugs that target other 1C-metabolism enzymes. This task is challenging however, as MTHFD2 shares high sequence identity with the constitutively expressed isozymes cytosolic MTHFD1 and mitochondrial MTHFD2L. In fact, one of the most potent MTHFD2 inhibitors reported to date, TH7299, is actually more active against MTHFD1 and MTHFD2L. While structures of MTHFD2 and MTHFD1 exist, no MTHFD2L structures are available. We determined the first structure of MTHFD2L and its complex with TH7299, which reveals the structural basis for its highly potent MTHFD2L inhibition. Detailed analysis of the MTHFD2L structure presented here clearly highlights the challenges associated with developing truly isoform-selective MTHFD2 inhibitors.
26.	Sehgelmeble, Fernando, et al. (author) Sulfonimidamides as Sulfonamides Bioisosteres : Rational Evaluation through Synthetic, in Vitro, and in Vivo Studies with γ-Secretase Inhibitors 2012 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:3, s. 396-399 Journal article (peer-reviewed)abstract The proof of the pudding: A proof-of-concept study using γ-secretase inhibitors as a model has shown that sulfonimidamides act as bioisosteres for sulfonamides. Detailed in vitro and in vivo profiling reveal that the sulfonimidamide motif imparts desirable properties such as decreased lipophilicity and plasma protein binding, accompanied by increased solubility. Our data support a wider use of this unique functional group in the design of new pharmacologically active agents.
27.	Sooriyaarachchi, Sanjeewani, et al. (author) Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with -Arylpropyl Analogues of Fosmidomycin 2016 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 11:18, s. 2024-2036 Journal article (peer-reviewed)abstract Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the -position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P.falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.
28.	Stary, Anna, et al. (author) Toward a Consensus Model of the hERG Potassium Channel 2010 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 5:3, s. 455-467 Journal article (peer-reviewed)abstract Malfunction of hERG potassium channels, due to inherited mutations or inhibition by drugs, can cause long QT syndrome, which can lead to life-threatening arrhythmias. A three-dimensional structure of hERG is a prerequisite to understand the molecular basis of hERG malfunction. To achieve a consensus model, we carried out an extensive analysis of hERG models based on various alignments of helix S5. We analyzed seven models using a combination of conventional geometry/packing/normality validation methods as well as molecular dynamics simulations and molecular docking. A synthetic test set with the X-ray crystal structure of K(v)1.2 with artificially shifted S5 sequences modeled into the structure served as a reference case. We docked the known hERG inhibitors (+)-cisapride, (S)-terfenadine, and MK-499 into the hERG models and simulation snapshots. None of the single analyses unambiguously identified a preferred model, but the combination of all three revealed that there is only one model that fulfils all quality criteria. This model is confirmed by a recent mutation scanning experiment (P. Ju, G. Pages, R. R Riek, P. C. Chen, A. M. Torres, R S. Bansal, S. Kuyucak, R W. Kuchel, J. I. Vandenberg, J. Biol. Chem. 2009, 284, 1000-1008).([1]) We expect the modeled structure to be useful as a basis both for computational studies of channel function and kinetics as well as the design of experiments.
29.	Sundén, Henrik, 1978, et al. (author) Design of a Highly Selective and Potent Class of Non-planar Estrogen Receptorβ Agonists 2013 In: Chemmedchem. - : Wiley. - 1860-7179 .- 1860-7187. ; 8:8, s. 1283-1294 Journal article (peer-reviewed)abstract Selective activation of the estrogen receptor (ER) could be a safe approach to hormone replacement therapy for both women and men, in contrast to the estrogens currently used for women which activate both ER and ER, occasionally causing severe side effects. cis-10-SR, was shown to have an EC50 value of <1nM, potency 100-fold higher than that of AC-131. Even more interestingly, compound trans-10-SS exhibited 1000-fold ER/ER selectivity while still maintaining good potency (approximate to 10nM). In addition, trans-10-SS showed only partial agonist activity (30-60% Eff.) toward ER at 10M. trans-10-SS appears to be the first molecule to take advantage of both conservative amino acid differences found in the - and -faces of the binding cavities of ER and ER beta.
30.	van Klaveren, Sjors, et al. (author) Selective Galectin-8N Ligands : The Design and Synthesis of Phthalazinone-d-Galactals 2021 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 17:6 Journal article (peer-reviewed)abstract Ligand selectivity among the highly conserved galectins has been an ever-challenging objective. For galectin-8, a protein prevalent in both pathology and tissue distribution, we report phthalazinone-galactals that show excellent selectivity for the galectin-8N-terminal domain. A dissection of structure–activity relationships of the phthalazinone and an extensive molecular dynamics meta-analysis accompany the discovery of the selective galectin-8N ligands presented here. These selective compounds will facilitate the study of galectin-8 biology and may have pharmaceutical relevance in the wide range of galectin-8 associated pathologies.
31.	Wacker, Soeren J., et al. (author) Identification of Selective Inhibitors of the Potassium Channel Kv1.1-1.2(3) by High-Throughput Virtual Screening and Automated Patch Clamp 2012 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:10, s. 1775-1783 Journal article (peer-reviewed)abstract Two voltage-dependent potassium channels, Kv1.1 (KCNA1) and Kv1.2 (KCNA2), are found to co-localize at the juxtaparanodal region of axons throughout the nervous system and are known to co-assemble in heteromultimeric channels, most likely in the form of the concatemer Kv1.11.2(3). Loss of the myelin sheath, as is observed in multiple sclerosis, uncovers the juxtaparanodal region of nodes of Ranvier in myelinated axons leading to potassium conductance, resulting in loss of nerve conduction. The selective blocking of these Kv channels is therefore a promising approach to restore nerve conduction and function. In the present study, we searched for novel inhibitors of Kv1.11.2(3) by combining a virtual screening protocol and electrophysiological measurements on a concatemer Kv1.11.2(3) stably expressed in Chinese hamster ovary K1 (CHO-K1) cells. The combined use of four popular virtual screening approaches (eHiTS, FlexX, Glide, and Autodock-Vina) led to the identification of several compounds as potential inhibitors of the Kv1.11.2(3) channel. From 89 electrophysiologically evaluated compounds, 14 novel compounds were found to inhibit the current carried by Kv1.11.2(3) channels by more than 80?% at 10 mu M. Accordingly, the IC50 values calculated from concentrationresponse curve titrations ranged from 0.6 to 6 mu M. Two of these compounds exhibited at least 30-fold higher potency in inhibition of Kv1.11.2(3) than they showed in inhibition of a set of cardiac ion channels (hERG, Nav1.5, and Cav1.2), resulting in a profile of selectivity and cardiac safety. The results presented herein provide a promising basis for the development of novel selective ion channel inhibitors, with a dramatically lower demand in terms of experimental time, effort, and cost than a sole high-throughput screening approach of large compound libraries.
32.	Wallner, Olov, et al. (author) Optimization of N-Piperidinyl-Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8-Oxo-Guanine DNA Glycosylase 1 2023 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 18:1 Journal article (peer-reviewed)abstract 8-oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8-oxoG could lead to G : C→T : A transversion, base removal is of utmost importance for cells to ensure genomic integrity. For cells with elevated levels of reactive oxygen species this dependency is further increased. In the past we and others have validated OGG1 as a target for inhibitors to treat cancer and inflammation. Here, we present the optimization campaign that led to the broadly used tool compound TH5487. Based on results from a small molecule screening campaign, we performed hit to lead expansion and arrived at potent and selective substituted N-piperidinyl-benzimidazolones. Using X-ray crystallography data, we describe the surprising binding mode of the most potent member of the class, TH8535. Here, the N-Piperidinyl-linker adopts a chair instead of a boat conformation which was found for weaker analogues. We further demonstrate cellular target engagement and efficacy of TH8535 against a number of cancer cell lines.
33.	Xia, Xin, et al. (author) In vivo Enhancement in Bioavailability of Atazanavir in the Presence of Proton-Pump Inhibitors using Mesoporous Materials 2012 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:1, s. 43-8 Journal article (peer-reviewed)abstract Matters of the HAART! The current treatment for human immunodeficiency virus (HIV), HAART, makes use of a combination of antiretroviral drugs, which are poorly soluble in aqueous media. Enhancing the solubility of such drugs through the use of mesoporous materials could lead to improved treatment efficiency and might provide a solution to the drug-drug interaction problems associated with these types of therapeutic regimes.
34.	Zeng, S., et al. (author) Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool 2020 In: ChemMedChem. - : John Wiley and Sons Ltd. - 1860-7179 .- 1860-7187. ; 15:16, s. 1608-1617 Journal article (peer-reviewed)abstract Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-fluorobenzonitrile was eventually generated and determined to have high potency, a fine pharmacokinetic profile, and a long-acting in vivo efficacy.
35.	Zhang, Ruiyan, et al. (author) Molecular Basis of the Receptor Interactions of Polysialic Acid (polySia), polySia Mimetics, and Sulfated Polysaccharides 2016 In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 11:9, s. 990-1002 Journal article (peer-reviewed)abstract Polysialic acid (polySia) and polySia glycomimetic molecules support nerve cell regeneration, differentiation, and neuronal plasticity. With a combination of biophysical and biochemical methods, as well as data mining and molecular modeling tech-niques, it is possible to correlate specific ligand–receptor inter-actions with biochemical processes and in vivo studies that focus on the potential therapeutic impact of polySia, polySia glycomimetics, and sulfated polysaccharides in neuronal dis-eases. With this strategy, the receptor interactions of polySia and polySia mimetics can be understood on a submolecular level. As the HNK-1 glycan also enhances neuronal functions, we tested whether similar sulfated oligo- and polysaccharides from seaweed could be suitable, in addition to polySia, for finding potential new routes into patient care focusing on an improved cure for various neuronal diseases. The knowledge obtained here on the structural interplay between polySia or sulfated polysaccharides and their receptors can be exploited to develop new drugs and application routes for the treatment of neurological diseases and dysfunctions.
36.	Briggner, Lars-Erik, et al. (author) Solid-State Perturbation for Solubility Improvement : A Proof of Concept 2011 In: ChemMedChem. - : Wiley. - 1860-7179. ; 6:1, s. 60-62 Journal article (peer-reviewed)abstract Simple and rational: The intrinsic solubility of a compound can be systematically improved by perturbing key interactions in its crystal structure. By carefully choosing the perturbation, the end result will be a molecule similar to the original one, but with significantly higher solubility. This methodology is demonstrated on a subset of benzodiazepines, resulting in significant improvement of their solubility.
37.	Carrasco, Marta, et al. (author) Probing the Azaaurone Scaffold against the Hepatic and Erythrocytic Stages of Malaria Parasites 2016 In: Chemmedchem. - : Wiley. - 1860-7179. ; 11:19, s. 2194-2204 Journal article (peer-reviewed)abstract The potential of azaaurones as dual-stage antimalarial agents was investigated by assessing the effect of a small library of azaaurones on the inhibition of liver and intraerythrocytic lifecycle stages of the malaria parasite. The whole series was screened against the blood stage of a chloroquine-resistant Plasmodium falciparum strain and the liver stage of P.berghei, yielding compounds with dual-stage activity and sub-micromolar potency against erythrocytic parasites. Studies with genetically modified parasites, using a phenotypic assay based on the P.falciparum Dd2-ScDHODH line, which expresses yeast dihydroorotate dehydrogenase (DHODH), showed that one of the azaaurone derivatives has the potential to inhibit the parasite mitochondrial electron-transport chain. The global urgency in finding new therapies for malaria, especially against the underexplored liver stage, associated with chemical tractability of azaaurones, warrants further development of this chemotype. Overall, these results emphasize the azaaurone chemotype as a promising scaffold for dual-stage antimalarials.
38.	Norinder, U, et al. (author) Prediction of ADMET Properties. 2006 In: ChemMedChem. - 1860-7179. ; 1:9, s. 920-937 Journal article (peer-reviewed)
39.	Zetterberg, Fredrik R., et al. (author) Monosaccharide Derivatives with Low-Nanomolar Lectin Affinity and High Selectivity Based on Combined Fluorine-Amide, Phenyl-Arginine, Sulfur-π, and Halogen Bond Interactions 2018 In: ChemMedChem. - : Wiley. - 1860-7179. ; 13:2, s. 133-137 Journal article (peer-reviewed)abstract The design of small and high-affinity lectin inhibitors remains a major challenge because the natural ligand binding sites of lectin are often shallow and have polar character. Herein we report that derivatizing galactose with un-natural structural elements that form multiple non-natural lectin-ligand interactions (orthogonal multipolar fluorine-amide, phenyl-arginine, sulfur-π, and halogen bond) can provide inhibitors with extraordinary affinity (low nanomolar) for the model lectin, galectin-3, which is more than five orders of magnitude higher than the parent galactose; moreover, is selective over other galectins.

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