title: HIV-1 Protease Dimerization Dynamics Reveals a Transient Druggable Binding Pocket at the Interface.
abstract: The binding mechanism of HIV-1 protease monomers leading to the catalytically competent dimeric enzyme has been investigated by means of state-of-the-art atomistic simulations. The emerging picture allows a deeper understanding of experimental observations and reveals that water molecules trapped at the interface have an important role in slowing down the kinetics of the association process. Unexpectedly, a cryptic binding pocket is identified at the interface of the complex, corresponding to a partially bound dimer that lacks enzymatic function. The pocket has a transient nature with a lifetime longer than 1 μs, and it displays very favorable druggability features. Docking as well as MM-GBSA free-energy calculations further support the possibility to target the new binding site by means of inhibitors able to prevent the complete dimerization by capturing the inactive conformation. This discovery could open the way to the rational design of a new class of anti-HIV drugs.
authors.affiliation: Sorbonne Universités, UPMC University Paris 6, CNRS - UMR 7590, IMPMC, F-75005 Paris, France.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pietrucci
authors.affiliation: Department of Physics, University of Cagliari, I-09042 Monserrato, Italy.
authors.forename: Attilio Vittorio
authors.initials: AV
authors.lastname: Vargiu
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, CH-1211 Geneva, Switzerland.
authors.forename: Agata
authors.initials: A
authors.lastname: Kranjc
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D000069454:Darunavir / Q000737:chemistry / Q000494:pharmacology; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D055503:Protein Multimerization; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides; D013816:Thermodynamics
chemical_list: D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D000069454:Darunavir; C107201:tipranavir