Diketo acid pharmacophore. 2. Discovery of structurally diverse inhibitors of HIV-1 integrase.

Because of its unique role in the viral replication process, HIV-1 integrase (IN) is an important antiretroviral drug target. The beta-diketo acid class of IN inhibitors has played a major role in validating IN as a legitimate target for antiretroviral drug design. S-1360 (1) and L-870,810 (2) are examples of beta-diketo acid related compounds to enter clinical trials. With an aim to discover novel lead compounds with diverse structural scaffolds, we employed common feature pharmacophore models using four known beta-diketo acid analogues including S-1360 (J. Med. Chem. 2005, 1, 111-120). The best-ranked pharmacophore model (Hypo1) contained a hydrophobic (HYA), an H-bond acceptor (HBA), and two H-bond donor (HBD) features. A search of a 3D database containing approximately 150,000 small molecules using Hypo1 found 1700 compounds that satisfied all the features of the pharmacophore query. Of the 1700 compounds, 110 were selected for in vitro screening studies on the basis of their docking scores, predicted binding location inside the active site of IN, and their druglike properties. Forty-eight compounds inhibited IN catalytic activities with an IC50 value less than 100 microM. Twenty-seven structurally diverse inhibitors are reported here. Out of the 27 compounds, 13 compounds inhibited strand transfer activity of IN with an IC50 value less than 30 microM. These compounds are novel, druglike, and readily amenable for synthetic optimization.