Binding modes of diketo-acid inhibitors of HIV-1 integrase: a comparative molecular dynamics simulation study.
Bottom Line: The Merck inhibitors can maintain either one or both of these ion-pair interaction features.The difference in potencies of the DKA inhibitors is thus attributed to the different binding modes at the catalytic site.Such structural information at atomic level, not only demonstrates the action modes of DKA inhibitors but also provides a novel starting point for structural-based design of HIV-1 IN inhibitors.
Affiliation: School of Chemistry and Chemical Engineering, David Keir Building, Queens University Belfast, Stranmillis Road, Belfast BT95AG, UK. firstname.lastname@example.orgShow MeSH
Mentions: There are two rotatable bonds around the methylene group of the L-731,988 anion, τ1 (C12C7C6N2) and τ2 (C7C6N2N1) (Fig. 2). Scanning of these two rotatable bonds with the HF/STO-3G method followed by single point energy calculation with B3LYP/6-31G*, gave two minima including a pair of s-cis extended isomers (The pyrrol nitrogen is in the cis position of the keto of the diketo acid part, with τ 1 of ∓104.5° and τ 2 ±72.2°) and a pair of s-trans folded isomers (τ 1 of ∓62.1̊ and τ 2 ±105.5°) (Fig. 3). The energy of the s-cis isomer is lower than the s-trans by 1.43 kcal mol−1. Optimization with bigger basis sets B3LYP/6-31G** and B3LYP/6-31+G** gave similar energy differences (1.43 and 1.96 kcal mol−1, respectively). Single point energy calculations at high level B3LYP/6-311+G (3df, 2p) based on the B3LYP/6-31+G** optimized geometries were carried out. The relative energy difference remains the same (1.55 kcal mol−1). The lower energy of s-cis isomers by DFT calculation with different basis set aforementioned indicated that they are more stable than the s-trans isomers. Both conformations were used to build the starting internal geometries of the IN-L-731,988 complex.
Affiliation: School of Chemistry and Chemical Engineering, David Keir Building, Queens University Belfast, Stranmillis Road, Belfast BT95AG, UK. email@example.com