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1.	Apprato, Giulia, et al. (författare) Exploring the chemical space of orally bioavailable PROTACs 2024 Ingår i: Drug Discovery Today. - : Elsevier. - 1359-6446 .- 1878-5832. ; 29:4 Forskningsöversikt (refereegranskat)abstract A principal challenge in the discovery of proteolysis targeting chimeras (PROTACs) as oral medications is their bioavailability. To facilitate drug design, it is therefore essential to identify the chemical space where orally bioavailable PROTACs are more likely to be situated. To this aim, we extracted structure-bioavailability insights from published data using traditional 2D descriptors, thereby shedding light on their potential and limitations as drug design tools. Subsequently, we describe cuttingedge experimental, computational and hybrid design strategies based on 3D descriptors, which show promise for enhancing the probability of discovering PROTACs with high oral bioavailability.
2.	Atilaw, Yoseph, et al. (författare) Solution Conformations Shed Light on PROTAC Cell Permeability 2021 Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 12:1, s. 107-114 Tidskriftsartikel (refereegranskat)abstract Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies of a VHL-based PROTAC (1), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that 1 populates elongated and polar conformations in solutions that mimic extra- and intracellular compartments. Conformations were folded and had a smaller polar surface area in chloroform, mimicking a cell membrane interior. Formation of intramolecular and nonclassical hydrogen bonds, π–π interactions, and shielding of amide groups from solvent all facilitate cell permeability by minimization of size and polarity. We conclude that molecular chameleonicity appears to be of major importance for 1 to enter into target cells.
3.	Begnini, Fabio, et al. (författare) Cell Permeability of Isomeric Macrocycles : Predictions and NMR Studies 2021 Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 12:6, s. 983-990 Tidskriftsartikel (refereegranskat)abstract Conformation-dependent 3D descriptors have been shown to provide better predictions of the physicochemical properties of macrocycles than 2D descriptors. However, the computational identification of relevant conformations for macrocycles is nontrivial. Herein, we report that the Caco- 2 cell permeability difference between a pair of diastereomeric macrocycles correlated with their solvent accessible 3D polar surface area and radius of gyration. The descriptors were calculated from the macrocycles’ solution- phase conformational ensembles and independently from ensembles obtained by conformational sampling. Calculation of the two descriptors for three other stereo- and regioisomeric macrocycles also allowed the correct ranking of their cell permeability. Methods for conformational sampling may thus allow ranking of passive permeability for moderatelyflexible macrocycles, thereby contributing to the prioritization of macro- cycles for synthesis in lead optimization.
4.	Begnini, Fabio, et al. (författare) Mining Natural Products for Macrocycles to Drug Difficult Targets 2021 Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:2, s. 1054-1072 Tidskriftsartikel (refereegranskat)abstract Lead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality in silico screening library that provides leads for difficult-to-drug targets. Two iterative rounds of docking of a carefully selected set of natural-product-derived cores led to the discovery of an uncharged macrocyclic inhibitor of the Keap1-Nrf2 protein- protein interaction, a particularly challenging target due to its highly polar binding site. The inhibitor displays cellular efficacy and is well-positioned for further optimization based on the structure of its complex with Keapl and synthetic access. We believe that our work will spur interest in using macrocyclic cores for in silico-based lead generation and also inspire the design of future macrocycle screening collections.
5.	Caron, Giulia, et al. (författare) Steering New Drug Discovery Campaigns : Permeability, Solubility, and Physicochemical Properties in the bRo5 Chemical Space 2021 Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 12:1, s. 13-23 Tidskriftsartikel (refereegranskat)abstract An increasing number of drug discovery programs concern compounds in the beyond rule of 5 (bRo5) chemical space, such as cyclic peptides, macrocycles, and degraders. Recent results show that common paradigms of property-based drug design need revision to be applied to larger and more flexible compounds. A virtual event entitled "Solubility, permeability and physico-chemical properties in the bRo5 chemical space" was organized to provide preliminary guidance on how to make the discovery of oral drugs in the bRo5 space more effective. The four speakers emphasized the importance of the bRo5 space as a source of new oral drugs and provided examples of experimental and computational methods specifically tailored for design and optimization in this chemical space.
6.	Danelius, Emma, et al. (författare) Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs 2020 Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 26:23, s. 5231-5244 Tidskriftsartikel (refereegranskat)abstract It has been hypothesised that drugs in the chemical space "beyond the rule of 5" (bRo5) must behave as molecular chameleons to combine otherwise conflicting properties, including aqueous solubility, cell permeability and target binding. Evidence for this has, however, been limited to the cyclic peptide cyclosporine A. Herein, we show that the non-peptidic and macrocyclic drugs roxithromycin, telithromycin and spiramycin behave as molecular chameleons, with rifampicin showing a less pronounced behaviour. In particular roxithromycin, telithromycin and spiramycin display a marked, yet limited flexibility and populate significantly less polar and more compact conformational ensembles in an apolar than in a polar environment. In addition to balancing of membrane permeability and aqueous solubility, this flexibility also allows binding to targets that vary in structure between species. The drugs' passive cell permeability correlates to their 3D polar surface area and corroborate two theoretical models for permeability, developed for cyclic peptides. We conclude that molecular chameleonicity should be incorporated in the design of orally administered drugs in the bRo5 space.
7.	Ermondi, Giuseppe, et al. (författare) Solubility prediction in the bRo5 chemical space : where are we right now? 2020 Ingår i: ADMET and DMPK. - : International Association of Physical Chemists (IAPC). - 1848-7718. ; 8:3, s. 207-214 Tidskriftsartikel (refereegranskat)abstract Modelling the solubility of compounds in the "beyond Rule of 5" (bRo5) chemical space is in its infancy and to date only a few studies have been reported in the literature. Based on our own results, and those already published, we conclude that consideration of conformational flexibility and chameleon like behaviour is important, but quantitative models that account for these properties remain to be developed. Inclusion of 3D information appears to be somewhat less important than for cell permeability and extremely challenging due to the difficulties of accurate conformational sampling in the bRo5 space. Currently, methods for modelling of solubility will have to be tailored to the set of investigated compounds.
8.	Jiang, Xiangyi, et al. (författare) Molecular design opportunities presented by solvent-exposed regions of target proteins 2019 Ingår i: Medicinal research reviews (Print). - : John Wiley & Sons. - 0198-6325 .- 1098-1128. ; 39:6, s. 2194-2238 Forskningsöversikt (refereegranskat)abstract Solvent-exposed regions, or solvent-filled pockets, within or adjacent to the ligand-binding sites of drug-target proteins provide opportunities for substantial modifications of existing small-molecular drug molecules without serious loss of activity. In this review, we present recent selected examples of exploitation of solvent-exposed regions of proteins in drug design and development from the recent medicinal-chemistry literature.
9.	Jiménez, Diego García, et al. (författare) Macrocycles in Drug Discovery?Learning from the Past for the Future 2023 Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:8, s. 5377-5396 Tidskriftsartikel (refereegranskat)abstract We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs are mainly used in infectious disease and oncology, while oncology is the major indication for the clinical candidates and in the literature Most macrocyclic drugs bind to targets that have difficult to drug binding sites. Natural products have provided 80-90% of the drugs and clinical candidates, whereas macrocycles in ChEMBL have less complex structures. Macrocycles usually reside in the beyond the Rule of 5 chemical space, but 30-40% of the drugs and clinical candidates are orally bioavailable. Simple bi-descriptor models, i.e., HBD <= 7 in combination with either MW < 1000 Da or cLogP > 2.5, distinguished orals from parenterals and can be used as filters in design. We propose that recent breakthroughs in conformational analysis and inspiration from natural products will further improve the de novo design of macrocycles.
10.	Ju, Han, et al. (författare) Identification of C5-NH2 Modified Oseltamivir Derivatives as Novel Influenza Neuraminidase Inhibitors with Highly Improved Antiviral Activities and Favorable Druggability 2021 Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:24, s. 17992-18009 Tidskriftsartikel (refereegranskat)abstract Our previous efforts have proved that modifications targeting the 150-cavity of influenza neuraminidase can achievemore potent and more selective inhibitors. In this work, foursubseries of C5-NH2modified oseltamivir derivatives weredesigned and synthesized to explore every region inside the 150-cavity. Among them, compound23dwas exceptionally potentagainst the whole panel of Group-1 NAs with IC50values rangingfrom 0.26 to 0.73 nM, being 15 & minus;53 times better than oseltamivircarboxylate (OSC) and 7 & minus;11 times better than zanamivir. Incellular assays,23dshowed more potent or equipotent antiviralactivities against corresponding virus strains compared to OSCwith no cytotoxicity. Furthermore,23dexhibited high metabolicstability in human liver microsomes (HLM) and low inhibitoryeffect on main cytochrome P450 enzymes. Notably,23ddisplayed favorable druggability in vivo and potent antiviral efficacy in the embryonated egg model and mice model. Overall,23dappears to be a promising candidate for the treatment of influenza virus infection.
11.	Peintner, Stefan, 1991-, et al. (författare) The Solvent Polarity Dependence of Macrocycles’ Conformations 2018 Konferensbidrag (refereegranskat)
12.	Peng, Cheng, et al. (författare) Conformation of the Macrocyclic Drug Lorlatinib in Polar and Nonpolar Environments : A MD Simulation and NMR Study 2019 Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 4:26, s. 22245-22250 Tidskriftsartikel (refereegranskat)abstract The replica exchange molecular dynamics (REMD) simulation is demonstrated to readily predict the conformations of the macrocyclic drug lorlatinib, as validated by solution NMR studies. In aqueous solution, lorlatinib adopts a conformer identical to its target bound structure. This conformer is stabilized by an extensive hydrogen bond network to the solvents. In chloroform, lorlatinib populates two conformers with the second one being less polar, which may contribute to lorlatinib’s ability to cross cell membranes.
13.	Petersen, Daniel, et al. (författare) Binding and intracellular transport of 25-hydroxycholesterol by Niemann-Pick C2 protein 2020 Ingår i: Biochimica et Biophysica Acta - Biomembranes. - : Elsevier BV. - 0005-2736 .- 1879-2642. ; 1862:2 Tidskriftsartikel (refereegranskat)abstract Side-chain oxidized cholesterol derivatives, like 25-hydroxycholesterol (25-OH-Chol) are important regulators of cellular cholesterol homeostasis. How transport of oxysterols through the endo-lysosomal pathway contributes to their biological function is not clear. The Niemann-Pick C2 protein (NPC2) is a small lysosomal sterol transfer protein required for export of cholesterol from late endosomes and lysosomes (LE/LYSs). Here, we show that 25-hydroxy-cholestatrienol, (25-OH-CTL), an intrinsically fluorescent analogue of 25-OH-Chol, becomes trapped in LE/LYSs of NPC2-deficient fibroblasts, but can efflux from the cells even in the absence of NPC2 upon removal of the sterol source. Fluorescence recovery after photobleaching (FRAP) of 25-OH-CTL in endo-lysosomes was rapid and extensive and only partially dependent on NPC2 function. Using quenching of NPC2's intrinsic fluorescence, we show that 25-OH-Chol and 25-OH-CTL can bind to NPC2 though with lower affinity compared to cholesterol and its fluorescent analogues, cholestatrienol (CTL) and dehydroergosterol (DHE). This is confirmed by calculations of binding energies which additionally show that 25-OH-CTL can bind in two orientations to NPC2, in stark contrast to cholesterol and its analogues. We conclude that NPC2's affinity for all sterols is energetically favored over their self-aggregation in the lysosomal lumen. Lysosomal export of 25-OH-Chol is not strictly dependent on the NPC2 protein.
14.	Poongavanam, Vasanthanathan, et al. (författare) Computational Analysis of Sterol Ligand Specificity of the Niemann Pick C2 Protein 2016 Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 55:36, s. 5165-5179 Tidskriftsartikel (refereegranskat)abstract Transport of cholesterol derived from hydrolysis of lipoprotein associated cholesteryl esters out of late endosomes depends critically on the function of the Niemann Pick Cl (NPC1) and C2 (NPC2) proteins. Both proteins bind cholesterol but also various other sterols and both-With strongly varying affinity: The molecular mechanisms under lying this multiligand specificity are not known. On the basis:Of the crystal structure of NPC2, we have here investigated structural details of NPC2 sterol interactions using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA): calculations. We found that an aliphatic side chain in the sterol ligand results in strong binding to NPC2, while side chain oxidized sterols gave weaker binding. Estradiol and the hydrophobic amine U18666A had the lowest affinity of all lested ligands and at the same time showed the highest flexibility within the NPC2 binding pocket. The binding affinity of all ligands correlated highly with their calculated partitioning coefficient (logP) between octanol/water phases and with the potential of sterols to stabilize the protein backbone. prom molecular dynamics simulations, we suggest a general mechanism for NPC2 mediated sterol transfer, in which Phe66, Val96, and Tyr100 act as reversible gate keepers. These residues stabilize the sterol in the binding pose via pi-pi stacking but move transiently. apart during sterol release. A computational mutation analysis revealed that the binding of various ligands depends critically on the same specific amino acid residues within the binding pocket providing shape complementary to sterols, but also on residues in distal regions of the protein.
15.	Poongavanam, Vasanthanathan, et al. (författare) Computational Modeling Explains the Multi Sterol Ligand Specificity of the N-Terminal Domain of Niemann-Pick C1-Like 1 Protein 2019 Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 4:25, s. 20894-20904 Tidskriftsartikel (refereegranskat)abstract Niemann-Pick C1 like 1 (NPC1L1) is a sterol transporter expressed in the apical membrane of enterocytes and hepatocytes. NPC1L1 resembles the lysosomal NPC1 protein including an N-terminal domain (NTD), which binds a variety of sterols. The molecular mechanisms underlying this multiligand specificity of the NTD of NPC1L1 (NPC1L1-NTD) are not known. On the basis of the crystal structure of NPC1L1-NTD, we have investigated the structural details of protein-sterol interactions using molecular mechanics Poisson Boltzmann surface area calculations here. We found a good agreement between experimental and calculated binding affinities with similar ranking of various sterol ligands. We defined hydrogen bonding of sterol ligands via the 3'-beta-hydroxy group inside the binding pose as instrumental in stabilizing the interaction. A leucine residue (LEU213) at the mouth of the binding pocket transiently opens to allow for the access of sterol into the binding pose. Our calculations also predict that NPC1L1-NTD binds polyene sterols, such as dehydroergosterol or cholestatrienol with high affinity, which validates their use in future experiments as close intrinsically fluorescent cholesterol analogs. A free energy decomposition and computational mutation analysis revealed that the binding of various sterols to NPC1L1-NTD depends critically on specific amino acid residues within the binding pocket. Some of these residues were previously detected as being relevant for intestinal cholesterol absorption. We show that clinically known mutations in the NPC1L1-NTD associated with lowered risk of coronary heart disease result in strongly reduced binding energies, providing a molecular explanation for the clinical phenotype.
16.	Poongavanam, Vasanthanathan, et al. (författare) Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations? 2018 Ingår i: Acs Omega. - : American Chemical Society (ACS). - 2470-1343. ; 3:9, s. 11742-11757 Tidskriftsartikel (refereegranskat)abstract Conformational flexibility is a major determinant of the properties of macrocycles and other drugs in beyond rule of 5 (bRo5) space. Prediction of conforrriations is essential for design of drugs in this space, and we have evaluated three tools for conformational sampling of la set of 10 bRo5 drugs and clinical candidates in polar and apolar environments. The distance-geometry based OMEGA was found to yield ensembles spanning larger structure and property spaces than the ensembles obtained by MOE LowModeMD (MOE) and MacroModel (MC). Both MC and OMEGA but not MOE generated different ensembles for polar and apolar environments. All three conforinational search methods generated conformers similar to the crystal structure conformers for 9 of the 10 compounds, with OMEGA performing somewhat better than MOE and MC. MOE and OMEGA found all six conformers of roxithromycin that were identified by NMR in aqueous solutions, whereas only OMEGA sampled the three conformers observed in chloroform. We suggest that characterization of conformers using molecular descriptors, e.g., the radius of gyration and polar surface area, is preferred to energy- or root-mean-square deviation-based methods for selection of biologically relevant conformers in drug discovery in bRo5 space.
17.	Poongavanam, Vasanthanathan, et al. (författare) Integrative approaches in HIV-1 non-nucleoside reverse transcriptase inhibitor design 2018 Ingår i: Wiley Interdisciplinary Reviews. Computational Molecular Science. - : Wiley. - 1759-0876 .- 1759-0884. ; 8:1 Tidskriftsartikel (refereegranskat)abstract The design of inhibitors for human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) is one of the most successful approaches for the treatment of HIV infections. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) constitute a prominent drug class, which includes nevirapine, delavirdine, efavirenz, etravirine, and rilpivirine approved for clinical use. However, the efficiency of many of these drugs has been undermined by drug-resistant variants of HIV-1 RT, and it therefore becomes inevitable to design novel drugs to cope with resistance. Here, we discuss various drug design strategies, which include traditional medicinal chemistry, computational chemistry, and chemical biology approaches. In particular, computational modeling approaches, including machine learning, empirical descriptors-based, force-field, ab initio, and hybrid quantum mechanics/molecular mechanics-based methods are discussed in detail. We foresee that these methods will have a major impact on efforts to guide the design and discovery of the next generation of NNRTIs that combat RT multidrug resistance.
18.	Poongavanam, Vasanthanathan, et al. (författare) Linker-Dependent Folding Rationalizes PROTAC Cell Permeability br 2022 Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:19, s. 13029-13040 Tidskriftsartikel (refereegranskat)abstract Proteolysis-targeting chimeras (PROTACs) must be cell permeable to reach their target proteins. This is challenging as the bivalent structure of PROTACs puts them in chemical space at, or beyond, the outer limits of oral druggable space. We used NMR spectroscopy and molecular dynamics (MD) simulations independently to gain insights into the origin of the differences in cell permeability displayed by three flexible cereblon PROTACs having closely related structures. Both methods revealed that the propensity of the PROTACs to adopt folded conformations with a low solvent-accessible 3D polar surface area in an apolar environment is correlated to high cell permeability. The chemical nature and the flexibility of the linker were essential for the PROTACs to populate folded conformations stabilized by intramolecular hydrogen bonds, pi-pi interactions, and van der Waals interactions. We conclude that MD simulations may be used for the prospective ranking of cell permeability in the design of cereblon PROTACs.
19.	Poongavanam, Vasanthanathan, Docent, et al. (författare) Molecular chameleons in drug discovery 2024 Ingår i: Nature Reviews Chemistry. - : Springer Nature. - 2397-3358. ; 8, s. 45-60 Forskningsöversikt (refereegranskat)abstract Molecular chameleons possess a flexibility that allows them to dynamically shield or expose polar functionalities in response to the properties of the environment. Although the concept of molecular chameleons was introduced already in 1970, interest in them has grown considerably since the 2010s, when drug discovery has focused to an increased extent on new chemical modalities. Such modalities include cyclic peptides, macrocycles and proteolysis-targeting chimeras, all of which reside in a chemical space far from that of traditional small-molecule drugs. Both cell permeability and aqueous solubility are required for the oral absorption of drugs. Engineering these properties, and potent target binding, into the larger new modalities is a more daunting task than for traditional small-molecule drugs. The ability of chameleons to adapt to different environments may be essential for success. In this Review, we provide both general and theoretical insights into the realm of molecular chameleons. We discuss why chameleons have come into fashion and provide a do-it-yourself toolbox for their design; we then provide a glimpse of how advanced in silico methods can support molecular chameleon design.
20.	Poongavanam, Vasanthanathan, et al. (författare) Opportunities and guidelines for discovery of orally absorbed drugs in beyond rule of 5 space 2018 Ingår i: Current Opinion in Chemical Biology. - : Elsevier BV. - 1367-5931. ; 44, s. 23-29 Forskningsöversikt (refereegranskat)abstract Recent years have seen a dramatic increase in the number of drugs approved in chemical space outside of Lipinski’s rule of 5, that is in what has been termed beyond rule of 5 (bRo5) space. The development of three major classes of oral drugs that treat HIV and HCV infections and the growing evidence that novel, difficult targets can be accessed has prompted research into understanding design of drugs displaying cell permeability, solubility and ultimately oral bioavailability in bRo5 space. Studies have found a consistent outer property limit for a reasonable chance of de novo designing oral bioavailability. In addition, several property-based guidelines, along with incorporation of chameleonic features, have emerged as strategies to aid design in bRo5 space. A more detailed understanding of the complex and environment dependent conformational landscape will likely be the focus of the next generation of guidelines allowing property predictions of ever more complex compounds. By pushing the boundaries of current orally designable chemical space we hope that discoveries will be made for fundamental science and also for discovery of novel therapeutics.
21.	Poongavanam, Vasanthanathan, et al. (författare) Predicting the permeability of macrocycles from conformational sampling – limitations of molecular flexibility 2020 Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 110:1, s. 301-313 Tidskriftsartikel (refereegranskat)abstract Macrocycles constitute superior ligands for targets that have flat binding sites but often require long synthetic routes, emphasizing the need for property prediction prior to synthesis. We have investigated the scope and limitations of machine learning classification models and of regression models for predicting the cell permeability of a set of de novo-designed, drug-like macrocycles. 2D-Based classification models, which are fast to calculate, discriminated between macrocycles that had low-medium and high permeability and may be used as virtual filters in early drug discovery projects. Importantly, stereo- and regioisomer were correctly classified. QSPR studies of two small sets of comparator drugs suggested that use of 3D descriptors, calculated from biologically relevant conformations, would allow development of more precise regression models for late phase drug projects. However, a 3D permeability model could only be developed for a rigid series of macrocycles. Comparison of NMR based conformational analysis with in silico conformational sampling indicated that this shortcoming originates from the inability of the molecular mechanics force field to identify the relevant conformations for flexible macrocycles. We speculate that a Kier flexibility index of ≤10 constitutes a current upper limit for reasonably accurate 3D prediction of macrocycle cell permeability.
22.	Poongavanam, Vasanthanathan, et al. (författare) Predictive Modeling of PROTAC Cell Permeability with Machine Learning 2023 Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 8:6, s. 5901-5916 Tidskriftsartikel (refereegranskat)abstract Approaches for predicting proteolysis targeting chimera (PROTAC) cell permeability are of major interest to reduce resource-demanding synthesis and testing of low-permeable PROTACs. We report a comprehensive investigation of the scope and limitations of machine learning-based binary classification models developed using 17 simple descriptors for large and structurally diverse sets of cereblon (CRBN) and von Hippel-Lindau (VHL) PROTACs. For the VHL PROTAC set, kappa nearest neighbor and random forest models performed best and predicted the permeability of a blinded test set with >80% accuracy (k >= 0.57). Models retrained by combining the original training and the blinded test set performed equally well for a second blinded VHL set. However, models for CRBN PROTACs were less successful, mainly due to the imbalanced nature of the CRBN datasets. All descriptors contributed to the models, but size and lipophilicity were the most important. We conclude that properly trained machine learning models can be integrated as effective filters in the PROTAC design process.
23.	Poongavanam, Vasanthanathan, et al. (författare) PROTAC cell permeability and oral bioavailability : a journey into uncharted territory 2022 Ingår i: Future Medicinal Chemistry. - : Future Science Ltd. - 1756-8919 .- 1756-8927. ; 14:3, s. 123-126 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
24.	Poongavanam, Vasanthanathan, et al. (författare) Structure-guided approach identifies a novel class of HIV-1 ribonuclease H inhibitors : binding mode insights through magnesium complexation and site-directed mutagenesis studies 2018 Ingår i: MedChemComm. - : ROYAL SOC CHEMISTRY. - 2040-2503 .- 2040-2511. ; 9:3, s. 562-575 Tidskriftsartikel (refereegranskat)abstract Persistent HIV infection requires lifelong treatment and among the 2.1 million new HIV infections that occur every year there is an increased rate of transmitted drug-resistant mutations. This fact requires a constant and timely effort in order to identify and develop new HIV inhibitors with innovative mechanisms. The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only viral encoded enzyme that still lacks an efficient inhibitor despite the fact that it is a well-validated target whose functional abrogation compromises viral infectivity. Identification of new drugs is a long and expensive process that can be speeded up by in silico methods. In the present study, a structure-guided screening is coupled with a similarity-based search on the Specs database to identify a new class of HIV-1 RNase H inhibitors. Out of the 45 compounds selected for experimental testing, 15 inhibited the RNase H function below 100 mu M with three hits exhibiting IC50 values < 10 mu M. The most active compound, AA, inhibits HIV-1 RNase H with an IC50 of 5.1 mu M and exhibits a Mg-independent mode of inhibition. Site-directed mutagenesis studies provide valuable insight into the binding mode of newly identified compounds; for instance, compound AA involves extensive interactions with a lipophilic pocket formed by Ala502, Lys503, and Trp (406, 426 and 535) and polar interactions with Arg557 and the highly conserved RNase H primer-grip residue Asn474. The structural insights obtained from this work provide the bases for further lead optimization.
25.	Sebastiano, Matteo Rossi, et al. (författare) Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 5 2018 Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:9, s. 4189-4202 Tidskriftsartikel (refereegranskat)abstract Conformational flexibility has been proposed to significantly affect drug properties outside rule-of-5 (Ro5) chemical space. Here, we investigated the influence of dynamically exposed polarity on cell permeability and aqueous solubility for a structurally diverse set of drugs and clinical candidates far beyond the Ro5, all of which populated multiple distinct conformations as revealed by X-ray crystallography. Efflux-inhibited (passive) Caco-2 cell permeability correlated strongly with the compounds’ minimum solvent-accessible 3D polar surface areas (PSA), whereas aqueous solubility depended less on the specific 3D conformation. Inspection of the crystal structures highlighted flexibly linked aromatic side chains and dynamically forming intramolecular hydrogen bonds as particularly effective in providing “chameleonic” properties that allow compounds to display both high cell permeability and aqueous solubility. These structural features, in combination with permeability predictions based on the correlation to solvent-accessible 3D PSA, should inspire drug design in the challenging chemical space far beyond the Ro5.
26.	Sethio, Daniel, et al. (författare) Simulation Reveals the Chameleonic Behavior of Macrocycles 2023 Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 63:1, s. 138-146 Tidskriftsartikel (refereegranskat)abstract Conformational analysis is central to the design of bioactive molecules. It is particularly challenging for macrocycles due to noncovalent transannular interactions, steric interactions, and ring strain that are often coupled. Herein, we simulated the conformations of five macrocycles designed to express a progression of increasing complexity in environment-dependent intramolecular interactions and verified the results against NMR measurements in chloroform and dimethyl sulfoxide. Molecular dynamics using an explicit solvent model, but not the Monte Carlo method with implicit solvation, handled both solvents correctly. Refinement of conformations at the ab initio level was fundamental to reproducing the experimental observations-standard state-of-the-art molecular mechanics force fields were insufficient. Our simulations correctly predicted the intramolecular interactions between side chains and the macrocycle and revealed an unprecedented solvent-induced conformational switch of the macrocyclic ring. Our results provide a platform for the rational, prospective design of molecular chameleons that adapt to the properties of the environment.
27.	Tyagi, Mohit, et al. (författare) Drug Syntheses Beyond the Rule of 5 2020 Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 26:1, s. 49-88 Forskningsöversikt (refereegranskat)abstract Drugs in the chemical space beyond the rule of 5 (bRo5) can modulate targets with difficult binding sites while retaining cell permeability and oral absorption. Reviewing the syntheses of bRo5 drugs approved since 1990 highlights synthetic chemistry's contribution to drug discovery in this space. Initially, bRo5 drugs were mainly natural products and semi-synthetic derivatives. Later, peptidomimetics and de novo designed compounds, that include up to seven chiral centres and macrocyclic rings became dominant. These drugs are prepared by total synthesis, sometimes by routes of more than 25 steps with stereocentres originating from the chiral pool, or being installed by chiral induction or enzymatic resolution. Interestingly, ring-closing metathesis proved to be the method of choice for macrocyclisation in hepatitis C virus protease inhibitors. We conclude that structural simplification, planning of synthetic routes regarding incorporation of stereocentres and macrocyclisation, as well as incorporation of structural knowledge and consideration of chameleonic properties in design, should facilitate drug discovery in bRo5 space.
28.	Tyagi, Mohit, et al. (författare) Toward the Design of Molecular Chameleons : Flexible Shielding of an Amide Bond Enhances Macrocycle Cell Permeability 2018 Ingår i: Organic Letters. - : AMER CHEMICAL SOC. - 1523-7060 .- 1523-7052. ; 20:18, s. 5737-5742 Tidskriftsartikel (refereegranskat)abstract A series of macrocycles inspired by natural products were synthesized to investigate how side-chains may shield amide bonds and influence cell permeability. NMR spectroscopy and X-ray crystallography revealed that the phenyl group of phenylalanine, but not the side-chains of homologous or aliphatic amino acids, shields the adjacent amide bond through an intramolecular NH-pi interaction. This resulted in increased cell permeability, suggesting that NH-pi interactions may be used in the design of molecular chameleons.
29.	Vijayan, R. S. K., et al. (författare) Enhancing preclinical drug discovery with artificial intelligence 2022 Ingår i: Drug Discovery Today. - : Elsevier. - 1359-6446 .- 1878-5832. ; 27:4, s. 967-984 Forskningsöversikt (refereegranskat)abstract Artificial intelligence (AI) is becoming an integral part of drug discovery. It has the potential to deliver across the drug discovery and development value chain, starting from target identification and reaching through clinical development. In this review, we provide an overview of current AI technologies and a glimpse of how AI is reimagining preclinical drug discovery by highlighting examples where AI has made a real impact. Considering the excitement and hyperbole surrounding AI in drug discovery, we aim to present a realistic view by discussing both opportunities and challenges in adopting AI in drug discovery.
30.	Wieske, Lianne H. E., 1994-, et al. (författare) Going Viral : An Investigation into the Chameleonic Behaviour of Antiviral Compounds 2023 Ingår i: Chemistry - A European Journal. - : Wiley-VCH Verlagsgesellschaft. - 0947-6539 .- 1521-3765. ; 29:8 Tidskriftsartikel (refereegranskat)abstract The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d6) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as “partial molecular chameleons” and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption.
31.	Wu, Gaochan, et al. (författare) Overview of Recent Strategic Advances in Medicinal Chemistry 2019 Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 62:21, s. 9375-9414 Tidskriftsartikel (refereegranskat)abstract Introducing novel strategies, concepts, and technologies that speed up drug discovery and the drug development cycle is of great importance both in the highly competitive pharmaceutical industry as well as in academia. This Perspective aims to present a "big-picture" overview of recent strategic innovations in medicinal chemistry and drug discovery.
32.	Yang, Jie, et al. (författare) Macrocyclic peptides as inhibitors of human LSD1 Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Lysine demethylase 1 (LSD1) regulates the degree of methylation of Lys4 of histone 3 in the nucleosome core particle. As LSD1 is overexpressed in certain cancers, inhibitors have potential for use as drugs. Guided by the structures of two peptidic ligands bound to LSD1 we prepared truncated, mono-substituted and macrocyclic peptides to find leads for development of specific and revserible inhibitors. Surface plasmon resonance biosensor analysis revealed that some stapled, macrocyclic peptides had up to 10-fold higher affinity for LSD1 than the corresponding linear native peptide. Furthermore, peptides cyclized by lactamization were low mM inhibitors of LSD1, with the most effective one being >25-fold more potent than the linear native reference.
33.	Yang, Jie, et al. (författare) Macrocyclic Peptides Uncover a Novel Binding Mode for Reversible Inhibitors of LSD1 2020 Ingår i: ACS Omega. - : AMER CHEMICAL SOC. - 2470-1343. ; 5:8, s. 3979-3995 Tidskriftsartikel (refereegranskat)abstract Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme which regulates the methylation of Lys4 of histone 3 (H3) and is overexpressed in certain cancers. We used structures of H3 substrate analogues bound to LSD1 to design macrocyclic peptide inhibitors of LSD1. A linear, Lys4 to Met-substituted, 11-mer (4) was identified as the shortest peptide distinctly interacting with LSD1. It was evolved into macrocycle 31, which was >40 fold more potent K-i = 2.3 mu M) than 4. Linear and macrocyclic peptides exhibited unexpected differences in structure-activity relationships for interactions with LSD1, indicating that they bind LSD1 differently. This was confirmed by the crystal structure of 31 in complex with LSD1-CoREST1, which revealed a novel binding mode at the outer rim of the LSD1 active site and without a direct interaction with FAD. NMR spectroscopy of 31 suggests that macrocyclization restricts its solution ensemble to conformations that include the one in the crystalline complex. Our results provide a solid basis for the design of optimized reversible LSD1 inhibitors.
34.	Zhang, Jian, et al. (författare) Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and-2 Influenza A Neuraminidases, Including a Drug-Resistant Variant 2018 Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:14, s. 6379-6397 Tidskriftsartikel (refereegranskat)abstract On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.

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