Computer-assisted drug design (CADD) methods will be applied to the discovery of new lead compounds to be used to inhibit the HIV integrase. HIV integrase inserts a fragment of viral DNA into the host genome thereby guaranteeing production of the necessary viral proteins. The enzyme operates as a multimer although design of inhibitors can be done with the structure of a monomer or dimer. A great deal of drug structure-activity information is available. These data along with the X-ray structure will be used for the CADD process. Both """"""""direct"""""""" and """"""""indirect"""""""" design methods will be used, as appropriate. These include 3D database searching and docking, binding energy calculations and ranking, and other methods. New methods will be developed where necessary. Among the specific aims to be addressed in the proposed work are the following. 1). Set up complete computational models of HIV- 1 integrase. These will include work on the catalytic subunit, complete monomer (with all three subunits), and multimers. This project will also involve the identification of the binding sites for the host and viral DNA as well as binding sites for the metal cofactors and the various inhibitors. Some compounds seem to inhibit formation of the active complex while others block various steps in the integration reaction. 2). Perform 3D database docking and screening study using the models created in previous project (i.e. catalytic subunit, monomer, multimer, etc.). Refine high-scoring compounds via more sophisticated methods. 3). Perform indirect drug design modeling based on the structures of known inhibitors and elucidated structure-activity relationships. This will involve the generation of a pharmacophore model for use as a target for 3D database screening. Use this approach to get new ideas but apply them to the X-ray structures. 4). Perform de novo drug design modeling in search of novel leads.
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