Pyrrolidine Derivatives as Plasmepsin Inhibitors: Binding Mode Analysis Assisted by Molecular Dynamics Simulations of a Highly Flexible Protein

ChemMedChem ◽  
2010 ◽  
Vol 5 (3) ◽  
pp. 443-454 ◽  
Author(s):  
Torsten Luksch ◽  
Andreas Blum ◽  
Nina Klee ◽  
Wibke E. Diederich ◽  
Christoph A. Sotriffer ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Mode ◽  
Mode Analysis ◽  
Flexible Protein ◽  
Dynamics Simulations

scholarly journals Identification of CDK7 Inhibitors from Natural Sources Using Pharmacoinformatics and Molecular Dynamics Simulations

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1197
Author(s):  
Vikas Kumar ◽  
Shraddha Parate ◽  
Gunjan Thakur ◽  
Gihwan Lee ◽  
Hyeon-Su Ro ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Affinity ◽  
Cost Effective ◽  
Binding Mode ◽  
Kinase Domain ◽  
Dynamics Simulation ◽  
Mode Analysis ◽  
Atp Binding Site ◽  
Dynamics Simulations

The cyclin-dependent kinase 7 (CDK7) plays a crucial role in regulating the cell cycle and RNA polymerase-based transcription. Overexpression of this kinase is linked with various cancers in humans due to its dual involvement in cell development. Furthermore, emerging evidence has revealed that inhibiting CDK7 has anti-cancer effects, driving the development of novel and more cost-effective inhibitors with enhanced selectivity for CDK7 over other CDKs. In the present investigation, a pharmacophore-based approach was utilized to identify potential hit compounds against CDK7. The generated pharmacophore models were validated and used as 3D queries to screen 55,578 natural drug-like compounds. The obtained compounds were then subjected to molecular docking and molecular dynamics simulations to predict their binding mode with CDK7. The molecular dynamics simulation trajectories were subsequently used to calculate binding affinity, revealing four hits—ZINC20392430, SN00112175, SN00004718, and SN00262261—having a better binding affinity towards CDK7 than the reference inhibitors (CT7001 and THZ1). The binding mode analysis displayed hydrogen bond interactions with the hinge region residues Met94 and Glu95, DFG motif residue Asp155, ATP-binding site residues Thr96, Asp97, and Gln141, and quintessential residue outside the kinase domain, Cys312 of CDK7. The in silico selectivity of the hits was further checked by docking with CDK2, the close homolog structure of CDK7. Additionally, the detailed pharmacokinetic properties were predicted, revealing that our hits have better properties than established CDK7 inhibitors CT7001 and THZ1. Hence, we argue that proposed hits may be crucial against CDK7-related malignancies.

scholarly journals Sampling of conformational ensemble for virtual screening using molecular dynamics simulations and normal mode analysis

2015 ◽  
Vol 7 (17) ◽  
pp. 2317-2331 ◽  
Author(s):  
Gautier Moroy ◽  
Olivier Sperandio ◽  
Shakti Rielland ◽  
Saurabh Khemka ◽  
Karen Druart ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
Normal Mode ◽  
Normal Mode Analysis ◽  
Mode Analysis ◽  
Conformational Ensemble ◽  
Dynamics Simulations

Revealing the binding mode between respiratory syncytial virus fusion protein and benzimidazole-based inhibitors

2015 ◽  
Vol 11 (7) ◽  
pp. 1857-1866
Author(s):  
Dingjue Ji ◽  
Wei Ye ◽  
HaiFeng Chen
Keyword(s):  
Molecular Dynamics ◽  
Respiratory Syncytial Virus ◽  
Fusion Protein ◽  
Molecular Dynamics Simulations ◽  
Binding Mode ◽  
Virus Fusion ◽  
Syncytial Virus ◽  
Dynamics Simulations

The binding mode between benzimidazole-based inhibitors and RSVF protein was revealed by docking and molecular dynamics simulations.

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