title: Refining the multiple protein structure pharmacophore method: consistency across three independent HIV-1 protease models.
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.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, 428 Church St., University of Michigan, Ann Arbor, 48109-1065, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Meagher
authors.forename: Michael G
authors.initials: MG
authors.lastname: Lerner
authors.forename: Heather A
authors.initials: HA
authors.lastname: Carlson
mesh_terms: D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease