title: Comparing the conformational behavior of a series of diastereomeric cyclic urea HIV-1 inhibitors using the low mode:monte carlo conformational search method.
abstract: The conformational flexibility of a series of diastereomeric cyclic urea HIV-1 protease inhibitors has been examined using the Low Mode:Monte Carlo conformational search method. Force fields were validated by a comparison of the energetic ordering of the minimum energy structures on the AMBER/GBSA(water), OPLSAA/GBSA(water) and HF/6-311G/SCRF(water) surfaces. The energetic ordering of the minima on the OPLSAA /GBSA(water) surface was in better agreement with the quantum calculations than the ordering on the AMBER/GBSA(water) surface. An ensemble of low energy structures was generated using OPLSAA/GBSA(water) and used to compare the molecular shape and flexibility of each diastereomer to the experimentally determined binding affinities and crystal structures of closely related systems. The results indicate that diastereomeric solution-phase energetic stability, conformational rigidity and ability to adopt a chair conformation correlate strongly with experimental binding affinities. Rigid body docking suggests that all of the diastereomers adopt solution-phase conformations suitable for alignment with the HIV-1 protease; however, these results indicate that the binding affinities are dependent upon subtle differences in the P1/P1' and P2/P2' substituent orientations.
authors.affiliation: Department of Chemistry, Hobart and William Smith Colleges, Geneva, New York 14456, USA. parish@hws.edu
authors.forename: Carol A
authors.initials: CA
authors.lastname: Parish
authors.forename: Matthew
authors.initials: M
authors.lastname: Yarger
authors.forename: Kent
authors.initials: K
authors.lastname: Sinclair
authors.forename: Myrianne
authors.initials: M
authors.lastname: Dure
authors.forename: Alla
authors.initials: A
authors.lastname: Goldberg
mesh_terms: D001665:Binding Sites; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D011487:Protein Conformation; D012996:Solutions; D013237:Stereoisomerism; D014508:Urea / Q000737:chemistry
chemical_list: D017320:HIV Protease Inhibitors; D012996:Solutions; D014508:Urea; D016333:HIV Protease