title: A priori prediction of activity for HIV-1 protease inhibitors employing energy minimization in the active site.
abstract: We have observed a high correlation between the intermolecular interaction energy (Einter) calculated for HIV-1 protease inhibitor complexes and the observed in vitro enzyme inhibition. A training set of 33 inhibitors containing modifications in the P1' and P2' positions was used to develop a regression equation which relates Einter and pIC50. This correlation was subsequently employed to successfully predict the activity of proposed HIV-1 protease inhibitors in advance of synthesis in a structure-based design program. This included a precursor, 47, to the current phase II clinical candidate, L-735,524 (51). The development of the correlation, its applications, and its limitations are discussed, and the force field (MM2X) and host molecular mechanics program (OPTIMOL) used in this work are described.
authors: Department of Molecular Systems, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors: M K
authors: MK
authors: Holloway
authors: J M
authors: JM
authors: Wai
authors: T A
authors: TA
authors: Halgren
authors: P M
authors: PM
authors: Fitzgerald
authors: J P
authors: JP
authors: Vacca
authors: B D
authors: BD
authors: Dorsey
authors: R B
authors: RB
authors: Levin
authors: W J
authors: WJ
authors: Thompson
authors: L J
authors: LJ
authors: Chen
authors: S J
authors: SJ
authors: deSolms
mesh_terms: D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry* / Q000648:ultrastructure; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease