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: Among the emerging HIV-1 IN inhibitors, 4-aryl-2,4-dioxobutanoic acid derivatives were found to have potent inhibitory activity on strand transfer. Two representative compounds are L-731,988 and L-708,906  (Fig. 2) from Merck. S-1360 , a potent IN inhibitor from Shionogi, also belongs to the diketo acid inhibitor family because the trizole part of S-1360 can be regarded as bioisostere of carboxlate (Fig. 2). It failed at phase II clinical trial due to rapid metabolism. Individual or combined mutation of T66I, M154I and S153Y confers resistance for the Merck inhibitors  and the mutation of N155S displays cross-resistance for the Merck inhibitors and L-870,810  (a potent strand transfer inhibitor of IN which was derived from pharmacophore search based on the DKA inhibitors but also failed at clinical trial). Nine combined mutations which include T66I, Q146K, S153A and others, all confer resistance to S-1360, indicating that these compounds bind at, or near, the enzyme active site . Two DKA derivatives Raltegravir (MK-0518)  and Elvitegravir (GS-9137) have been recently approved as anti-AIDS drug or in clinical trials . Q148K and T66I conferred the highest resistance to both drugs while S153Y conferred relatively greater resistance to Elvitegravir than Raltegravir . Mutation of Tyr143 is known to confer resistance to Raltegravir . The drug resistance to Raltegravir conferred by mutation of N155H, was attributed to the disruption of the metal cofactors with the catalytic carboxylate at the active centre of IN . The mutations of IN which confer resistance to DKA inhibitors and the derivative drugs are listed in Table S1.
Affiliation: School of Chemistry and Chemical Engineering, David Keir Building, Queens University Belfast, Stranmillis Road, Belfast BT95AG, UK. firstname.lastname@example.org