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Mol Biosyst. 2014 Mar 4;10(3):526-36. doi: 10.1039/c3mb70418a. Epub 2014 Jan 6.

Blocking the interaction between HIV-1 integrase and human LEDGF/p75: mutational studies, virtual screening and molecular dynamics simulations.

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Computer-Aided Drug Design and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi-630 004, Tamil Nadu, India.


HIV-1 integrase (IN) mediates integration of viral cDNA into the host cell genome, an essential step in the retroviral life cycle. The human lens epithelium-derived growth factor (LEDGF/p75) is a co-factor of HIV-1 IN that plays a crucial role in viral integration. Because of its crucial role in early steps of HIV replication, the IN-LEDGF/p75 interaction represents an attractive target for anti-HIV drug discovery. In this study, the IN-LEDGF/p75 interaction was studied by in silico mutational studies and molecular dynamics simulations. The results showed that all of the key residues in the LEDGF/p75 binding pocket of IN protein are important for stabilization of the complex. Structure-based virtual screening against HIV-1 IN using the ChemBridge database was performed through three different protocols of docking simulations with varying precisions and computational intensities. Six compounds based on the docking score, binding affinity and pharmacokinetic parameters were selected and an analysis of the interactions with key amino acid residues of IN was carried out. Subsequently, molecular dynamics simulations of these compounds in the LEDGF/p75 binding site of IN were carried out in order to study the stability of complexes and their hydrogen bonding interactions. IN residues Glu170, His171, and Thr174 in chain A as well as Gln95 and Thr125 in chain B were discovered to play important roles in the binding of compounds. These findings could be helpful for blocking IN-LEDGF/p75 interaction, and provide a method for avoiding viral resistance and cross-resistance.

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