Computational Modelling

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Principal Investigator/Program Director (Last, First, Middle): Chaiken, Irwin M. / LaLonde, Judith M. DESCRIPTION:. The key objective of this project is to rationally design small-molecule antagonists that block the interaction between the human CD4 cell surface receptor and the gp120 envelope protein of HIV-1 as potential therapeutics for the treatment of AIDS. In the previous grant period the integrated program project has elaborated the mechanism of inhibition of two compound sets. Novel modes of inhibition of CD4-gp120 binding have also been discovered in the form of peptide, mini-[roteins and protein conjugates. In the continuation period Core A computational modeling will elaborate existing inhibitors and provide the necessary designs and modeling of protein conformations to convert these conjugates, peptides and mini- proteins into productive inhibitors. The proposed specific aims of Core A are: 1) Use computational methods to develop novel compounds of competitive Phe43 mimetic compounds and allosteric inhibitors and 2) Generate models of unliganded and gp120 bound conformations, and use these to identify and evaluate novel target sites for structure based inhibitor design. Meeting objective 1 will require close interaction with the Smith, Chaiken and Hendrickson groups in conjunction with experimental virology assessments from the Sodroski group as we carry out iterations of the design-synthesize-test drug discovery process. Meeting objective 2 will require experimental feedback from the Freire group, Chaiken and Sodroski groups. Future co-crystals of gp120 and antagonists from the Hendrickson group will provide potential new directions for refining the antagonist designs. The dynamic process of feedback between modeling, synthesis and experiment in the program project will lead to an integrated and effective design of an HIV antagonist.