Induced‐Fit Docking Approach Provides Insight into the Binding Mode and Mechanism of Action of HIV‐1 Integrase Inhibitors

Abstract

A three-dimensional model of a complex between HIV-1 integrase (IN), viral DNA, and metal ions that we recently built was used as a target for a docking method (induced-fit docking, IFD) that accurately predicts ligand binding modes and concomitant structural changes in the receptor. Six different well-known integrase strand transfer inhibitors (INSTIs): L-708,906, L-731,988, S-1360, L-870,810, raltegravir, and elvitegravir were thus used as ligands for our docking simulations. The obtained IFD results are consistent with the mechanism of action proposed for this class of IN inhibitors, that is, metal chelating/binding agents. This study affords new insight into the possible mechanism of inhibition and binding conformations for INSTIs. The impact on our hypothesis of specific mutations associated with IN inhibitor resistance was also evaluated. All these findings might have implications for integrase-directed HIV-1 drug discovery efforts.

Structure-based modeling of the functional HIV-1 intasome and its inhibition

“…We can only assume that the rather dramatic rearrangement in adenosine positioning upon INSTI engagement lies outside the myriad of possibilities sampled by automated docking programs. Accordingly, comparing the positioning of RAL and EVG in our models with results of recent INSTI docking studies (28,39,40) reveals strikingly different binding modes.…”

“…Predecessor diketo acids moreover displayed affinity for binding to the intasome as compared with free IN, highlighting a role for the viral DNA end in forming the complete drug interaction site (16). Because of the importance of discerning the underlying mechanism of drug binding, numerous studies have modeled INSTIs at the HIV-1 IN active site, the most recent of these focusing on RAL and EVG (28,39,40). PFV intasome activity, as well as cell infection by PFV, is inhibited by RAL and EVG (41).…”

Structure-Analysis of the HIV-1 Integrase Y143C/R Raltegravir Resistance Mutation in Association with the Secondary Mutation T97A

“…The isopropyl and methyl-oxadiazole groups of raltegravir are involved in hydrophobic and -stacking interactions with the side chains of Pro214 and Tyr212, respectively (15). Numerous studies have modeled INSTIs at the HIV-1 IN active site (3,16,29,34), with the most recent one focusing on raltegravir and elvitegravir. The binding of raltegravir in the context of these dynamic models of both the WT and the G140S/Q148H drugresistant enzyme has been studied (29).…”

Challenges and advances in computational docking: 2009 in review

“…Schrodinger's Induced Fit Docking (IFD) Workflow (23,24) involves rigid receptor docking with Glide (25,26), combined with protein-ligand complex minimization with the homology modeling module Prime (24). IFD has been successfully used for studies of kinases (27,28), HIV-1 Integrase (29), heat shock protein 90 (30), monoacylglycerol lipase (31).…”