Identification of HIV-1 Integrase Inhibitors Based on a Four-Point Pharmacophore

Abstract

The rapid emergence of human immunodeficiency virus (HIV) strains resistant to available drugs implies that effective treatment modalities will require the use of a combination of drugs targeting different sites of the HIV life cycle. Because the virus cannot replicate without integration into a host chromosome, HIV-1 integrase (IN) is an attractive therapeutic target. Thus, an effective IN inhibitor should provide additional benefit in combination chemotherapy. A four-point pharmacophore has been identified based on the structures of quinalizarin and purpurin, which were found to be potent IN inhibitors using both a preintegration complex assay and a purified enzyme assay in vitro. Searching with this four-point pharmacophore in the 'open' part of the National Cancer Institute three-dimensional structure database produced 234 compounds containing the pharmacophore. Sixty of these compounds were tested for their inhibitory activity against IN using the purified enzyme; 19 were found to be active against IN with IC 50 values of less than 100 µM, among which 10 had IC 50 values of less than 10 µM. These inhibitors can further serve as leads, and studies are in progress to design novel inhibitors based on the results presented in this study.

Diverse Small Molecule Inhibitors of Human Apurinic/Apyrimidinic Endonuclease APE1 Identified from a Screen of a Large Public Collection

“…The flavonoid derivative MLS000737267, also known as galloflavin (a product derived from gallic acid oxidation), has been shown to inhibit human immunodeficiency virus integrase at a low-micromolar IC 50 [46]. Phenanthrenes derived from orchid plant species, bearing similar chemical features to the trimethoxyphenanthrene-diol hit MLS000863573, have recently been highlighted for their anti-inflammatory activity, presumably by inhibiting the lipopolysacharide-induced nitric oxide production in murine macrophages [47].…”

Antiviral Activity of Substituted Salicylanilides - A Review

“…More compounds containing N-substituted salicylamide or salicylhydrazide pharmacophore were described to affect HIV integrase, but some were inactive. It implicates that the activity is not only the function of pharmacophore presence [65,[78][79][80][81]. For example, unsubstituted salicylamide is inactive, whereas salicylhydrazide presented a moderate activity [80].…”

QSAR Models at the US FDA/NCTR

“…By the end of last century, the advancement in computer technology and the generation of a huge amount of scientific data [5,6] progressed the field of QSAR to a new height. A lot of QSAR methods have been developed and applied by the scientific research community and in regulatory sciences [7][8][9][10], e.g., pharmacophore modeling [11][12][13][14][15], molecular docking [16][17][18][19], CoMFA [19], classification tree model [20], decision forest [21][22][23][24][25][26][27], and support vector machine [28], to name a few.…”