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  • Title: Refining the multiple protein structure pharmacophore method: consistency across three independent HIV-1 protease models.
    Author: Meagher KL, Lerner MG, Carlson HA.
    Journal: J Med Chem; 2006 Jun 15; 49(12):3478-84. PubMed ID: 16759090.
    Abstract:
    Developing methods to incorporate protein flexibility into structure-based drug design is an important challenge. Our approach uses multiple protein structures (MPS) to create a receptor-based pharmacophore model of the desired target. We have previously demonstrated the success of the method by applying it to human immunodeficiency virus-1 protease (HIV-1p). Our models, based on an apo structure, discriminated known HIV-1p inhibitors from druglike inactive compounds and also accurately identified bound conformations of known inhibitors. Here, we test the method by applying it to all three unbound crystal structures of HIV-1p. We have also improved our method with denser probe mapping of the binding site and refined our selection criteria for pharmacophore elements. Our improved protocol has led to the development of a consistent 8-site pharmacophore model for HIV-1p, which is independent of starting structure, and a robust MPS pharmacophore method that is more amenable to automation.
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