title: Identifying the molecular mechanics and binding dynamics characteristics of potent inhibitors to HIV-1 protease.
abstract: Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the primary inhibition targets for chemotherapy of AIDS because of its critical role in the replication cycle of the HIV. In this work, a combinatory coarse-grained and atomistic simulation method was developed for dissecting molecular mechanisms and binding process of inhibitors to the active site of HIV-1 PR, in which 35 typical inhibitors were trialed. We found that the molecular size and stiffness of the inhibitors and the binding energy between the inhibitors and PR play important roles in regulating the binding process. Comparatively, the smaller and more flexible inhibitors have larger binding energy and higher binding rates; they even bind into PR without opening the flaps. In contrast, the larger and stiffer inhibitors have lower binding energy and lower binding rate, and their binding is subjected to the opening and gating of the PR flaps. Furthermore, the components of binding free energy were quantified and analyzed by their dependence on the molecular size, structures, and hydrogen bond networks of inhibitors. Our results also deduce significant dynamics descriptors for determining the quantitative structure and property relationship in potent drug ligands for HIV-1 PR inhibition.
authors.affiliation: Biomechanics and Biomaterials Laboratory, Department of Applied Mechanics, Beijing Institute of Technology, China.
authors.forename: Dechang
authors.initials: D
authors.lastname: Li
authors.forename: Ming S
authors.initials: MS
authors.lastname: Liu
authors.forename: Baohua
authors.initials: B
authors.lastname: Ji
authors.forename: Keh-Chih
authors.initials: KC
authors.lastname: Hwang
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Huang
mesh_terms: D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1