| 1. |
- Collins, Patrick M., et al.
(författare)
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Taloside Inhibitors of Galectin-1 and Galectin-3
- 2012
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0285 .- 1747-0277. ; 79:3, s. 339-346
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-1 and galectin-3 have roles in cancer and inflammation. Galectin-1 has recently emerged as a significant protein produced by tumour cells to promote tumour development, angiogenesis and metastasis and consequently represents an important target to inhibit. The design of inhibitors targeting the carbohydrate recognition domain that is known to recognize galactose is an important approach in the fight against cancer. Based on the analysis of crystal structures, we pursued the concept that if the galactose was replaced with talose (the C2 epimer of galactose) as a scaffold, then O2 substituents would be directed closer to the protein surface and provide opportunity to design inhibitors that are more specific towards particular galectins. Our elucidation of X-ray crystal structures of two of our synthesized talosides in complex with galectin-1 and galectin-3 provides the first atomic information on the interactions of galectins, and indeed any protein, with talosides. These results have enabled a structure-based rationale for the specificity differences shown by galectin-1 and galectin-3 towards these talosides and demonstrate new opportunities for further exploitation as specific inhibitors of galectins.
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| 2. |
- Rogers, Kathleen E., et al.
(författare)
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Novel Cruzain Inhibitors for the Treatment of Chagas' Disease
- 2012
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 80:3, s. 398-405
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Tidskriftsartikel (refereegranskat)abstract
- The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T.similar to cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas disease.
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| 3. |
- Albericio, Fernando, et al.
(författare)
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Trishomocubane amino acid as a β-turn scaffold
- 2008
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Ingår i: Chemical biology & drug design. - : Wiley. - 1747-0277 .- 1747-0285. ; 71:2, s. 125-130
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis and X-ray structure of two diasteriomeric heptapeptides [Ac-Ala-Ala-Ala-(R/S)-Cage-Ala-Ala-Ala-NH2] with a trishomocubane amino acid as a beta-turn scaffold are reported. The amino acid was synthesized as a racemate and two diastereomeric peptides were obtained. The two peptides were separated by preparative high-pressure liquid chromatography and crystals suitable for X-ray analysis were grown for both diasteriomeric peptides. In general, both the peptides satisfy the criteria for beta-turn conformations. Five of the six Ala residues of both cage peptide crystals satisfy the criteria for 3(10)-helix characteristics and the cage amino acid residue satisfied the m-helix classification. These experimental results confirm previous theoretical studies in our laboratory which predicted that the cage moiety would be a strong/active beta-turn inducer.
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| 4. |
- Bergström, Maria, et al.
(författare)
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Cholera toxin inhibitors studied with High-performance liquid affinity chromatography: arobust method to evaluate receptor-ligand interactions
- 2009
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 73:1, s. 132-141
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Tidskriftsartikel (refereegranskat)abstract
- Anti-adhesion drugs may be an alternative to antibiotics to control infection of micro-organisms. The well-characterized interaction between cholera toxin and the cellular glycolipid GM1 makes it an attractive model for inhibition studies in general. In this report, we demonstrate a high-performance liquid affinity chromatography approach called weak affinity chromatography to evaluate cholera toxin inhibitors. The cholera toxin B-subunit was covalently coupled to porous silica and a (weak) affinity column was produced. The K(D) values of galactose and meta-nitrophenyl alpha-d-galactoside were determined with weak affinity chromatography to be 52 and 1 mm, respectively, which agree well with IC(50) values previously reported. To increase inhibition potency multivalent inhibitors have been developed and the interaction with multivalent glycopolypeptides was also evaluated. The affinity of these compounds was found to correlate with the galactoside content but K(D) values were not obtained because of the inhomogeneous response and slow off-rate from multivalent interactions. Despite the limitations in obtaining direct K(D) values of the multivalent galactopolypeptides, weak affinity chromatography represents an additional and valuable tool in the evaluation of monovalent as well as multivalent cholera toxin inhibitors. It offers multiple advantages, such as a low sample consumption, high reproducibility and short analysis time, which are often not observed in other methods of analysis.
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| 5. |
- Fayad, Walid, et al.
(författare)
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Identification of Agents that Induce Apoptosis of Multicellular Tumour Spheroids : Enrichment for Mitotic Inhibitors with Hydrophobic Properties
- 2011
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 78:4, s. 547-557
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Tidskriftsartikel (refereegranskat)abstract
- Cell-based anticancer drug screening generally utilizes rapidly proliferating tumour cells grown as monolayer cultures. Hit compounds from such screens are not necessarily effective on hypoxic and slowly proliferating cells in 3-D tumour tissue. The aim of this study was to examine the potential usefulness of 3-D cultured tumour cells for anticancer drug screening. We used colon carcinoma multicellular spheroids containing hypoxic and quiescent cells in core areas for this purpose. Three libraries (similar to 11 000 compounds) were screened using antiproliferative activity and/or apoptosis as end-points. Screening of monolayer and spheroid cultures was found to identify different sets of hit compounds. Spheroid screening enriched for hydrophobic compounds: median XLogP values of 4.3 and 4.4 were observed for the hits in two independent screening campaigns. Mechanistic analysis revealed that the majority of spheroid screening hits were microtubuli inhibitors. One of these inhibitors was examined in detail and found to be effective against non-dividing cells in the hypoxic centres of spheroids. Spheroid screening represents a conceptually new strategy for anticancer drug discovery. Our findings have implications for drug library design and hit selection in projects aimed to develop drugs for the treatment of solid tumours.
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| 6. |
- Gach, Katarzyna, et al.
(författare)
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The influence of opioids on urokinase plasminogen activator on protein and mRNA level in MCF-7 breast cancer cell line.
- 2009
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Ingår i: Chemical biology & drug design. - : Wiley. - 1747-0285 .- 1747-0277. ; 74:4, s. 390-6
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Tidskriftsartikel (refereegranskat)abstract
- Urokinase plasminogen activator plays a key role in tumor-associated processes, increasing cancer cell invasion and metastasis, and is therefore used as a marker in cancer prognosis. In this study, we have determined the effect of mu-opioid receptor agonists and antagonists on the urokinase plasminogen activator secretion in MCF-7 cell line. It was shown that mu-opioid receptor agonists, such as morphine and endomorphins, greatly stimulate urokinase plasminogen activator secretion, while naloxone and MOR-selective antagonists elicit the opposite effect. The same tendency was observed also on the urokinase plasminogen activator mRNA level. However, neither agonists nor antagonists had any effect on proliferation of MCF-7 cells. The findings reported in this study may be useful in designing further experiments aimed at elucidating the role of the opioid system in cancer cells.
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| 7. |
- Hossain, M. Akhter, et al.
(författare)
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The structural and functional role of the B-chain C-terminal arginine in the relaxin-3 peptide antagonist, R3(B Delta 23-27)R/I5.
- 2009
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 73:1, s. 46-52
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Tidskriftsartikel (refereegranskat)abstract
- Relaxin-3, a member of the insulin superfamily, is involved in regulating stress and feeding behavior. It is highly expressed in the brain and is the endogenous ligand for the receptor RXFP3. As relaxin-3 also interacts with the relaxin receptor RXFP1, selective agonists and antagonists are crucial for studying the physiological function(s) of the relaxin-3/RXFP3 pair. The analog R3(B Delta 23-27)R/I5, in which a C-terminally truncated human relaxin-3 (H3) B-chain is combined with the INSL5 A-chain, is a potent selective RXFP3 antagonist and has an Arg residue remaining on the B-chain C-terminus as a consequence of the recombinant protein production process. To investigate the role of this residue in the RXFP3 receptor binding and activation, the analogs R3(B Delta 23-27)R/I5 and R3(B Delta 23-27)R containing the B-chain C-terminal Arg as well as R3(B Delta 23-27)/I5 and R3(B Delta 23-27), both lacking the Arg, were chemically assembled and their secondary structure and receptor activity assessed. The peptides generally had a similar conformation but those with the extra Arg residue displayed a significantly increased affinity for the RXFP3. Interestingly, in contrast to R3(B Delta 23-27)R and R3(B Delta 23-27)R/I5, the peptide R3(B Delta 23-27) is a weak agonist. This suggests that the C-terminal Arg, although increasing the affinity, alters the manner in which the peptide binds to the receptor and thereby prevents activation, giving R3(B Delta 23-27)R/I5 its potent antagonistic activity.
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| 8. |
- Li, Yadi, et al.
(författare)
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Virtual and In vitro bioassay screening of phytochemical inhibitors from flavonoids and isoflavones against Xanthine oxidase and Cyclooxygenase-2 for gout treatment
- 2013
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Ingår i: Chemical Biology and Drug Design. - : John Wiley & Sons. - 1747-0277 .- 1747-0285. ; 81:4, s. 537-544
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Tidskriftsartikel (refereegranskat)abstract
- Synthetic drugs such as allopurinol and benzbroarone are commonly used to treat the complex pathogenesis of gout, a metabolic disease that results from an inflammation of the joints caused by precipitation of uric acid. We seek to discover novel phytochemicals that could treat gout, by targeting the xanthine oxidase (XO) and cyclooxygenase 2 (COX-2) enzymes. In this study, we report the screening of 9 compounds of flavonoids from the ZINC and PubChem databases (containing 2,092 flavonoids) using the iGEMDOCK software tool against the XO and COX-2 3D protein structures. Each compound was also evaluated by an in vitro bioassay testing the inhibition of XO and COX-2. Myricetin and luteolin were found to be the potential dual inhibitors of XO and COX-2 as demonstrated by IC50: 62.7 and 3.29μg/mL (XO) / 70.8 and 16.38μg/mL (COX-2), respectively. In addition, structure activity relationships and other important factors of the flavonoids binding to the active site of XO and COX-2 were discussed, which is expected for further rational drug design.
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| 9. |
- Delbro, Dick, et al.
(författare)
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The influence of opioids on urokinase plasminogen activator on protein and mRNA level in MCF-7 breast cancer cell line
- 2009
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Ingår i: Chemical Biology and Drug Design. - 1747-0277 .- 1747-0285. ; 74:4, s. 390-396
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Tidskriftsartikel (refereegranskat)abstract
- Urokinase plasminogen activator plays a key role intumor-associated processes, increasing cancer cellinvasion and metastasis, and is therefore used as amarker in cancer prognosis. In this study, we havedetermined the effect of mu-opioid receptor agonistsand antagonists on the urokinase plasminogen activatorsecretion in MCF-7 cell line. It was shown thatmu-opioid receptor agonists, such as morphine andendomorphins, greatly stimulate urokinase plasminogenactivator secretion, while naloxone andMOR-selective antagonists elicit the oppositeeffect. The same tendency was observed also onthe urokinase plasminogen activator mRNA level.However, neither agonists nor antagonists had anyeffect on proliferation of MCF-7 cells. The findingsreported in this study may be useful in designingfurther experiments aimed at elucidating the roleof the opioid system in cancer cells
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| 10. |
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| 11. |
- Fawzy, Iten M., et al.
(författare)
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Newly Designed and Synthesized Curcumin Analogs with in vitro Cytotoxicity and Tubulin Polymerization Activity
- 2015
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 86:1, s. 860-870
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Tidskriftsartikel (refereegranskat)abstract
- Novel curcumin analogs with 4-piperidone ring were designed, synthesized, and evaluated for their cytotoxic activities against five different cancer cell lines. 3,5-bis(4-Hydroxy-3-methoxybenzylidene)-4-oxo-N-phenylpiperidine-1-carbothioamide (XIIe) exhibited considerable cytotoxic activity with IC50 values in 1-2.5m range. In silico and in vitro, studies were also performed to predict the binding affinity of the target compounds to the -chain of tubulin receptor (PDB code 1SA1) and their abilities to affect microtubules polymerization cycle. 3,5-bis(3-Iodo-5-methoxy-4-propoxybenzylidene)-N-acetylpiperidin-4-one (VIIa) was found to exert 93.3% inhibition of tubulin and destabilization of microtubules in vitro compared to vincristine while, 3,5-bis(3,4,5-trimethoxybenzylidene)-N-benzoylpiperidin-4-one (XIIc) showed high potency in a differentway where it exerted 94.8% stabilization of microtubules in vitro compared to positive control paclitaxel.
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| 12. |
- Hiremathad, Asha, et al.
(författare)
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Development of coumarin-benzofuran hybrids as versatile multitargeted compounds for the treatment of Alzheimer's Disease
- 2018
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Ingår i: Chemical Biology and Drug Design. - : John Wiley & Sons. - 1747-0277 .- 1747-0285. ; 92:2, s. 1497-1503
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD), the most common cause of dementia, is a neurodegenerative disorder characterized by progressive deterioration of memory and cognition. The evidenced multifactorial nature of AD has been considered the main reason for the absence of cure so far. Therefore, the development of novel hybrids to treat the disease is very much essential. Focusing on this, a novel series of coumarin-benzofuran hybrids have been designed and screened as anti-Alzheimer's disease agents. The strategy is to obtain an effective mimetic of donepezil, which is acetylcholinesterase inhibitor. Herein, the two main scaffolds namely coumarin and benzofuran are known pharmacophore moieties and we have performed their molecular design, pharmacokinetic descriptor studies for drug-likeliness. Further, in vitro studies such as antioxidant capacity, acetylcholinesterase (AChE) inhibition and amyloid-beta (A beta) self-aggregation inhibition have also been performed. Most importantly, these studies revealed that the newly synthesized hybrids can be versatile and promising drug-like moieties as efficient anti-AD agents.
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| 13. |
- Kumalo, Hezekiel M, et al.
(författare)
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Heat Shock Protein 90 (Hsp90) as Anti-cancer Target for Drug Discovery: An Ample Computational Perspective.
- 2015
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0285 .- 1747-0277. ; 86:5, s. 1131-1160
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Forskningsöversikt (refereegranskat)abstract
- There are over 100 different types of cancer, and each is classified based on the type of cell that is initially affected. If left untreated, cancer can result in serious health problems and eventually death. Recently the paradigm of cancer chemotherapy has evolved to use a combination approach, which involves the use of multiple drugs each of which targets an individual protein. Inhibition of heat shock protein 90 (Hsp90) is one of the novel key cancer targets. Because of its ability to target several signaling pathways, Hsp90 inhibition emerged as a useful strategy to treat a wide variety of cancers. Molecular modeling approaches and methodologies have become "close counterparts" to experiments in drug design and discovery workflows. A wide-range of molecular modeling approaches have been developed, each of which has different objectives and outcomes. In this review, we provide an up-to-date systematic overview on the different computational models implemented towards the design of Hsp90 inhibitors as anti-cancer agents. Although this is the main emphasis of this review, different topics such as; background and current statistics of cancer, different anti-cancer targets including Hsp90, the structure and function of Hsp90 from an experimental perspective e.g. X-ray and NMR are also addressed in this report. To the best of our knowledge, this review is the first account, which comprehensively outlines various molecular modeling efforts directed towards identification of anti-cancer drugs targeting Hsp90. We believe that the information, methods and perspectives highlighted in this report would assist researchers in the discovery of potential anti-cancer agents. This article is protected by copyright. All rights reserved.
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| 14. |
- Mahanti, Mukul, et al.
(författare)
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Flap Dynamics in Aspartic Proteases : A Computational Perspective
- 2016
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0285 .- 1747-0277. ; 88:2, s. 159-177
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Forskningsöversikt (refereegranskat)abstract
- Recent advances in biochemistry and drug design have placed proteases as one of the critical target groups for developing novel small-molecule inhibitors. Among all proteases, aspartic proteases have gained significant attention due to their role in HIV/AIDS, malaria, Alzheimer's disease, etc. The binding cleft is covered by one or two β-hairpins (flaps) which need to be opened before a ligand can bind. After binding, the flaps close to retain the ligand in the active site. Development of computational tools has improved our understanding of flap dynamics and its role in ligand recognition. In the past decade, several computational approaches, for example molecular dynamics (MD) simulations, coarse-grained simulations, replica-exchange molecular dynamics (REMD) and metadynamics, have been used to understand flap dynamics and conformational motions associated with flap movements. This review is intended to summarize the computational progress towards understanding the flap dynamics of proteases and to be a reference for future studies in this field.
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| 15. |
- Rasmussen, Michel, et al.
(författare)
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The stereospecific interaction sites and target specificity of cGMP analogs in mouse cortex
- 2022
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 99:2, s. 206-221
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Tidskriftsartikel (refereegranskat)abstract
- cGMP interactors play a role in several pathologies and may be targets for cGMP analog-based drugs, but the success of targeting depends on the biochemical stereospecificity between the cGMP-analog and the interactor. The stereospecificity between general cGMP analogs—or such that are selectivity-modified to obtain, for example, inhibitory actions on a specific target, like the cGMP-dependent protein kinase—have previously been investigated. However, the importance of stereospecificity for cGMP-analog binding to interactors is not known. We, therefore, applied affinity chromatography on mouse cortex proteins utilizing analogs with cyclic phosphate (8-AET-cGMP, 2-AH-cGMP, 2′-AHC-cGMP) and selectivity-modified analogs with sulfur-containing cyclic phosphorothioates (Rp/Sp-8-AET-cGMPS, Rp/Sp-2′-AHC-cGMPS) immobilized to agaroses. The results illustrate the cGMP analogs' stereospecific binding for PKG, PKA regulatory subunits and PKA catalytic subunits, PDEs, and EPAC2 and the involvement of these in various KEGG pathways. For the seven agaroses, PKG, PKA regulatory subunits, and PKA catalytic subunits were more prone to be enriched by 2-AH-, 8-AET-, Rp-8-AET-, and Sp-8-AET-cGMP, whereas PDEs and EPAC2 were more likely to be enriched by 2-AH-, Rp-2′-AHC-, and Rp-8-AET-cGMP. Our findings help elucidate the stereospecific-binding sites essential for the interaction between individual cGMP analogs and cGMP-binding proteins, as well as the cGMP analogs’ target specificity, which are two crucial parameters in drug design.
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| 16. |
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| 17. |
- Wang, Xin, et al.
(författare)
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Synthesis and Evaluation of Derivatives of the Proteasome Deubiquitinase Inhibitor b-AP15
- 2015
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0277 .- 1747-0285. ; 86:5, s. 1036-1048
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Tidskriftsartikel (refereegranskat)abstract
- The ubiquitin-proteasome system (UPS) is increasingly recognized as a therapeutic target for the development of anticancer therapies. The success of the 20S proteasome core particle (20S CP) inhibitor bortezomib in the clinical management of multiple myeloma has raised the possibility of identifying other UPS components for therapeutic intervention. We previously identified the small molecule b-AP15 as an inhibitor of 19S proteasome deubiquitinase (DUB) activity. Building upon our previous data, we performed a structure-activity relationship (SAR) study on b-AP15 and identified VLX1570 as an analog with promising properties, including enhanced potency and improved solubility in aqueous solution. In silico modeling was consistent with interaction of VLX1570 with key cysteine residues located at the active sites of the proteasome DUBs USP14 and UCHL5. VLX1570 was found to inhibit proteasome deubiquitinase activity in vitro in a manner consistent with competitive inhibition. Furthermore, using active-site-directed probes, VLX1570 also inhibited proteasome DUB activity in exposed cells. Importantly, VLX1570 did not show inhibitory activity on a panel of recombinant non-proteasome DUBs, on recombinant kinases, or on caspase-3 activity, suggesting that VLX1570 is not an overtly reactive general enzyme inhibitor. Taken together, our data shows the chemical and biological properties of VLX1570 as an optimized proteasome DUB inhibitor.
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| 18. |
- Xue, Yuhan, et al.
(författare)
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Computational insights into the different catalytic activities of CYP3A4 and CYP3A5 toward schisantherin E
- 2019
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Ingår i: Chemical Biology and Drug Design. - : Blackwell Publishing. - 1747-0277 .- 1747-0285. ; 93:5, s. 854-864
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Tidskriftsartikel (refereegranskat)abstract
- The cytochromes CYP3A4 and CYP3A5 share 84% sequence identity, but they exhibit different catalytic activities toward some substrates. Schisantherin E (SE) was recently identified as a selective substrate of CYP3A5, which exhibited catalytic efficiency that was more than 23 times higher than CYP3A4. At present, however, the structural determinants responsible for the different catalytic activities of the two enzymes toward SE have not been fully understood. In this study, a combination of molecular docking, molecular dynamic simulations, and binding free energy calculation was performed on the CYP3A4/CYP3A5-SE systems to investigate the issue. The results demonstrate that Ser119 in CYP3A4 and Glu374 in CYP3A5 formed direct hydrogen bonding with SE, respectively. Additionally, one water molecule located between the B-C loop and the I helix mediated different hydrogen-bonding networks between CYP3A4/3A5 and SE. The residue differences (Phe/Leu108 and Leu/Phe210) triggered the distinct conformational changes of the Phe-cluster residues, especially Phe213 and Phe215, which formed stronger hydrophobic interactions with SE in CYP3A5. The calculated binding free energies were consistent with the experimental results.
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| 19. |
- Zhang, Daoguang, et al.
(författare)
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Discovery of novel 5-methyl-1H-pyrazole derivatives as potential anti-prostate cancer agents : design, synthesis, molecular modeling and biological evaluation
- 2018
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Ingår i: Chemical Biology and Drug Design. - : John Wiley & Sons. - 1747-0277 .- 1747-0285. ; 91:6, s. 1113-1124
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Tidskriftsartikel (refereegranskat)abstract
- Androgen receptor (AR) signaling functions as a core driving force for the progression of prostate cancer (PCa), and AR has been proved to be an effective therapeutic target even for castration resistant prostate cancer (CRPC). Herein, structural modification via a fragments splicing strategy was performed based on two lead compounds T3 and 10e, leading to the discovery of a series of 5-methyl-1H-pyrazole derivatives. AR reporter gene assay revealed compounds A13 and A14 as potent AR antagonists. Some of the compounds in this series inhibited growth of PCa LNCaP cells more efficiently than enzalutamide. A13 and A14 also showed improved metabolic stability comparing with 10e in human liver microsomes.
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