scholarly journals Synthesis, structure–activity relationship and binding mode analysis of 4-thiazolidinone derivatives as novel inhibitors of human dihydroorotate dehydrogenase

MedChemComm ◽  
2017 ◽  
Vol 8 (6) ◽  
pp. 1297-1302 ◽  
Author(s):  
Fanxun Zeng ◽  
Tiantian Qi ◽  
Chunyan Li ◽  
Tingfang Li ◽  
Honglin Li ◽  
...  
Keyword(s):  
Binding Mode ◽  
Structure Activity Relationship ◽  
Mode Analysis ◽  
Activity Relationship ◽  
Dihydroorotate Dehydrogenase ◽  
Structure Activity

A series of 4-thiazolidinone derivatives were synthesized and evaluated as novel human dihydroorotate dehydrogenase (hDHODH) inhibitors.

Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure–Activity Relationship and Binding Mode Analysis

2020 ◽  
Vol 63 (4) ◽  
pp. 1576-1596 ◽  
Author(s):  
Radka Houštecká ◽  
Martin Hadzima ◽  
Jindřich Fanfrlík ◽  
Jiří Brynda ◽  
Lenka Pallová ◽  
...  
Keyword(s):  
Cathepsin D ◽  
Binding Mode ◽  
Structure Activity Relationship ◽  
Mode Analysis ◽  
Activity Relationship ◽  
Structure Activity ◽  
Human Cathepsin

scholarly journals Structural Optimization and Structure–Activity Relationship of 4-Thiazolidinone Derivatives as Novel Inhibitors of Human Dihydroorotate Dehydrogenase

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2780
Author(s):  
Fanxun Zeng ◽  
Lina Quan ◽  
Guantian Yang ◽  
Tiantian Qi ◽  
Letian Zhang ◽  
...  
Keyword(s):  
Binding Mode ◽  
Structure Activity Relationship ◽  
Immunosuppressive Drugs ◽  
Activity Relationship ◽  
Dihydroorotate Dehydrogenase ◽  
Structure Activity ◽  
Docking Method ◽  
Ic50 Values ◽  
Relationship Of ◽  
Molecular Docking Method

Human dihydroorotate dehydrogenase (hDHODH), one of the attractive targets for the development of immunosuppressive drugs, is also a potential target of anticancer drugs and anti-leukemic drugs. The development of promising hDHODH inhibitors is in high demand. Based on the unique binding mode of our previous reported 4-thiazolidinone derivatives, via molecular docking method, three new series 4-thiazolidinone derivatives were designed and synthesized as hDHODH inhibitors. The preliminary structure–activity relationship was investigated. Compound 9 of biphenyl series and compound 37 of amide series displayed IC50 values of 1.32 μM and 1.45 μM, respectively. This research will provide valuable reference for the research of new structures of hDHODH inhibitors.

Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors

2017 ◽  
Vol 60 (17) ◽  
pp. 7371-7392 ◽  
Author(s):  
Agnès Joncour ◽  
Nicolas Desroy ◽  
Christopher Housseman ◽  
Xavier Bock ◽  
Natacha Bienvenu ◽  
...  
Keyword(s):  
Binding Mode ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity ◽  
Pyridine Series

scholarly journals Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Benzopyran-Based Inhibitors

2021 ◽  
Vol 8 ◽  
Author(s):  
Sudarsana Reddy Vanga ◽  
Johan Åqvist ◽  
Anders Hallberg ◽  
Hugo Gutiérrez-de-Terán
Keyword(s):  
Binding Affinity ◽  
Binding Mode ◽  
Structure Activity Relationship ◽  
Site Directed Mutagenesis ◽  
Activity Relationship ◽  
Structural Basis ◽  
Binding Model ◽  
Linear Interaction ◽  
Structure Activity ◽  
Energy Perturbation

Inhibition of the insulin-regulated aminopeptidase (IRAP) improves memory and cognition in animal models. The enzyme has recently been crystallized and several series of inhibitors reported. We herein focused on one series of benzopyran-based inhibitors of IRAP known as the HFI series, with unresolved binding mode to IRAP, and developed a robust computational model to explain the structure-activity relationship (SAR) and potentially guide their further optimization. The binding model here proposed places the benzopyran ring in the catalytic binding site, coordinating the Zn2+ ion through the oxygen in position 3, in contrast to previous hypothesis. The whole series of HFI compounds was then systematically simulated, starting from this binding mode, using molecular dynamics and binding affinity estimated with the linear interaction energy (LIE) method. The agreement with experimental affinities supports the binding mode proposed, which was further challenged by rigorous free energy perturbation (FEP) calculations. Here, we found excellent correlation between experimental and calculated binding affinity differences, both between selected compound pairs and also for recently reported experimental data concerning the site directed mutagenesis of residue Phe544. The computationally derived structure-activity relationship of the HFI series and the understanding of the involvement of Phe544 in the binding of this scaffold provide valuable information for further lead optimization of novel IRAP inhibitors.

scholarly journals Computational study of binding of epothilone A to β-tubulin.

2011 ◽  
Vol 58 (2) ◽  
Author(s):  
Karol Kamel ◽  
Andrzej Kolinski
Keyword(s):  
Rational Design ◽  
Computational Study ◽  
Binding Mode ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Electron Crystallography ◽  
Structure Activity ◽  
Epothilone A ◽  
Computer Aided ◽  
Β Tubulin

Understanding the interactions of epothilones with β-tubulin is crucial for computer aided rational design of macrocyclic drugs based on epothilones and epothilone derivatives. Despite numerous structure-activity relationship investigations we still lack substantial knowledge about the binding mode of epothilones and their derivatives to β-tubulin. In this work, we reevaluated the electron crystallography structure of epothilone A/β-tubulin complex (PDB entry 1TVK) and proposed an alternative binding mode of epothilone A to β-tubulin that explains more experimental facts.

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