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. email@example.comShow MeSH
Mentions: The time evolution of the distance between the NZ atom of Lys159 and the carboxylate oxygen of Merck inhibitors, or the triazole nitrogen atom of S-1360 is shown in Fig. 7. In the IN bound with 5-ClTEP structure, the distance between Lys159 and the acidic nitrogen of the tetrazole ring of 5-ClTEP is 2.8 Å, which indicates that the ligand forms a salt bridge with Lys159. The distances between Lys159 and the acid part of the Merck inhibitors and S-1360 were examined for the conformation averaged over the last 500 ps of the MD simulations. The residue Lys159 was brought in close proximity to the carboxylate group of L-731,988 with the distance between the ammonia nitrogen of Lys159 and the carboxylate oxygen around 4.5 Å in the IN-L-731,988 complex, implying only a weak salt bridge interaction is formed. In IN bound with L-708,906, the Lys159 was brought even closer to the carboxylate of the ligand and the distance between the ammonia group of Lys159 and the carboxylate group of the ligand was shortened to 2.6 Å, indicating a stronger salt bridge was formed. In the average structures of IN-S-1360 complex the charged ammonia group of Lys159 moved closer to the acidic group of S-1360, with the distance between ammonia nitrogen and triazole nitrogen around 2.9 Å, indicating that a strong salt bridge interaction had formed.
Affiliation: School of Chemistry and Chemical Engineering, David Keir Building, Queens University Belfast, Stranmillis Road, Belfast BT95AG, UK. firstname.lastname@example.org