Identification of Adjacent NNRTI Binding Pocket in Multi-mutated HIV1- RT Enzyme Model: An in silico Study
| Autor: | Utsab Debnath, R F Kamil, Saroj Verma, Yenamandra S. Prabhakar |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation In silico Mutant Quantitative Structure-Activity Relationship Computational biology Molecular Dynamics Simulation 01 natural sciences 03 medical and health sciences Virology Drug Discovery Humans Computer Simulation Homology modeling Amino Acids Tyrosine Binding site Binding Sites 010405 organic chemistry Chemistry Wild type Hydrogen Bonding HIV Reverse Transcriptase 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology Infectious Diseases Docking (molecular) Enzyme model HIV-1 Reverse Transcriptase Inhibitors |
| Zdroj: | Current HIV Research. 16:121-129 |
| ISSN: | 1570-162X |
| Popis: | Introduction: A possible strategy to combat mutant strains is to have a thorough structural evaluation before and after mutations to identify the diversity in the non-nucleoside inhibitor binding pocket and their effects on enzyme-ligand interactions to generate novel NNRTI’s accordingly. Objective: The primary objective of this study was to find effects of multiple point mutations on NNRTI binding pocket. This study included the contribution of each individual mutation in NNIBP that propose an adjacent binding pocket which can be used to discover novel NNRTI derivatives. Methods: An in Silico model of HIV-1 RT enzyme with multiple mutations K103N, Y181C and Y188L was developed and evaluated. Two designed NNRTI pyridinone derivatives were selected as ligands for docking studies with the homology model through alignment based docking and residue based docking approaches. Binding pockets of wild type HIV-1 RT and multi-mutated homology model were compared thoroughly. Result and Discussion: K103N mutation narrowed the entrance of NNRTI binding pocket and forbade electrostatic interaction with α amino group of LYS103. Mutations Y181C and Y188L prevented NNRTI binding by eliminating aromatic π interactions offered by tyrosine rings. Docking study against new homology model suggested an adjacent binding pocket with combination of residues in palm and connection domains. This pocket is approximately 14.46Å away from conventional NNRTI binding site. Conclusion: Increased rigidity, steric hindrance and losses of important interactions cumulatively prompt ligands to adapt adjacent NNRTI binding pocket. The proposed new and adjacent binding pocket is identified by this study which can further be evaluated to generate novel derivatives. |
| Databáze: | OpenAIRE |
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