Discovery of Inhibitors To Block Interactions of HIV-1 Integrase with Human LEDGF/p75 via Structure-Based Virtual Screening and Bioassays

Abstract

This study aims to identify inhibitors that bind at the interface of HIV-1 integrase (IN) and human LEDGF/p75, which represents a novel target for anti-HIV therapy. To date, only a few such inhibitors have been reported. Here structure-based virtual screening was performed to search for the inhibitors from an in-house library of natural products and their derivatives. Among the 38 compounds selected by our strategy, 18 hits were discovered. The two most potent inhibitors showed IC(50) values at 0.32 and 0.26 μM, respectively. Three compounds were subsequently selected for anti-HIV assays, among which (E)-3-(2-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (NPD170) showed the highest antiviral activity (EC(50) = 1.81 μM). The antiviral mechanism of these compounds was further explored, and the results validated that the compounds interrupted the binding of transfected IN to endogenous LEDGF/p75. These findings could be helpful for anti-HIV drug discovery.

Montmorillonite Clay-Promoted, Solvent-Free Cross-Aldol Condensations under Focused Microwave Irradiation

“…These properties include antineoplastic [5][6][7], antimalarial [8], antiviral (HIV) [9,10], antibacterial [4,11,12], antioxidant [12] and anti-inflammatory [4,13] activities, among others. These compounds are also flexible scaffolds for the construction of five-and six-membered rings or their subsequent elaboration into polycyclic systems [14,15].…”

Anti-HIV Drug Development Through Computational Methods

“…Eighteen hits were discovered through AlphaScreen bioassays. One compound, (E)-3-(2-chlorophenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (NPD170), showed the highest anti-viral activity (EC50=1.81 μM) (39). Although the therapeutic index (TI) of NPD170 was not very high (4.88), this was a good case for the discovery of an anti-HIV compound via virtual screening.…”

“…Via structure-based virtual screening, 38 compounds were selected from an in-house library containing 1,430 natural products and their derivatives. The virtual screening was performed using an induced fit model to discover inhibitors that target IN−LEDGF/p75 interactions (39). Eighteen hits were discovered through AlphaScreen bioassays.…”

HPLC, open column chromatography, and LC-ESI-MS separation patterns and a new method of estimation of a phytoconstituent from Heiba (Ficus pomifera Wall.)

“…This method can be applied for estimation of compounds for which standard is not available. Triterpenoids have been reported to have cytotoxic property against cancer cell lines [17]; some compounds exhibited anti-human immunodeficiency virus (HIV) activity on HIV-infected cells [18,19]. Study of separation and estimation of compounds such as compound 1 is important.…”