Discovery of HIV-1 Integrase Inhibitors through a Novel Combination of Ligand and Structure-based Drug Design

Title: Discovery of HIV-1 Integrase Inhibitors through a Novel Combination of Ligand and Structure-based Drug Design

Volume: 1 Issue: 3

Author(s): A. Brigo, G. Iurcu Mustata, J. M. Briggs and S. Moro

Affiliation:

Keywords: high throughput docking, hiv Integrase, diketo acid hiv Integrase inhibitors

Abstract: Over the past 10 years, classical computer-aided molecular design methods have not been frequently applied for the discovery of novel HIV-1 integrase (IN) inhibitors, due to the intrinsic challenges that this enzyme presents. Therefore, a novel approach that combines the chemical information of known integrase inhibitors with the enzymes detailed 3D structure in a stepwise fashion is proposed: (I) use of a pharmacophore model (PM), which takes into account in a weighted fashion the chemical features of known ligands, in analogous manner to the to search the Maybridge and the NCI 3D databases; (II) drug-likeness optimization; (III) virtual high-throughput screening of the hits matching the PM query against 1QS4 wild-type IN structure using different Docking/Scoring combinations; (IV) visual inspection and selection of the hits in function of: binding free energies; binding mode type within the active site; retrieval among the best 20% hits in more than 6 Docking/Scoring protocols at the same time. This approach aims at a rational selection of new potential HIV-1 integrase inhibitors.

Cite this article as:

Brigo A., Mustata Iurcu G., Briggs M. J. and Moro S., Discovery of HIV-1 Integrase Inhibitors through a Novel Combination of Ligand and Structure-based Drug Design, Medicinal Chemistry 2005; 1 (3) . https://dx.doi.org/10.2174/1573406053765440