Premium
Allosteric mechanism of quinoline inhibitors for HIV RT ‐associated RN ase with MD simulation and dynamics fluctuation network
Author(s) -
Cai Yi,
Liu Hao,
Chen Haifeng
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13146
Subject(s) - allosteric regulation , reverse transcriptase , chemistry , retrovirus , molecular dynamics , rnase p , rnase h , viral replication , mechanism of action , in silico , virus , biology , biochemistry , stereochemistry , biophysics , enzyme , in vitro , virology , rna , gene , computational chemistry
The human immunodeficiency virus ( HIV ) is a retrovirus which infects T lymphocyte of human body and causes immunodeficiency. Reverse transcriptase inhibitors ( RTI s) can inhibit some functions of RT , preventing virus synthesis (double‐stranded DNA ), so that HIV virus replication can be reduced. Experimental results indicate a series of benzimidazole‐based inhibitors which target HIV RT‐associated RN ase to inhibit the reverse transcription of HIV virus. However, the allosteric mechanism is still unclear. Here, molecular dynamics simulations and dynamics fluctuation network analysis were used to reveal the binding mode between the inhibitors and RT‐associated RN ase. The most active molecule has more hydrophobic and electrostatic interactions than the less active inhibitor. Dynamics correlation network analysis indicates that the most active inhibitor perturbs the network of RT‐associated RN ase and decreases the correlation of nodes. 3D‐ QSAR model suggests that two robust and reliable models were constructed and validated by independent test set. 3D‐ QSAR model also shows that bulky negatively charged or hydrophilic substituent is favorable to bioactivity. These results reveal the allosteric mechanism of quinoline inhibitors and help to improve the bioactivity.