Computational studies of darunavir into HIV-1 protease and DMPC bilayer: Necessary conditions for effective binding and the role of the flaps

Leonis, G; Czyznikowska, Z; Megariotis, G; Reis, H; Papadopoulos, MG

dc.contributor.author	Leonis, G	en
dc.contributor.author	Czyznikowska, Z	en
dc.contributor.author	Megariotis, G	en
dc.contributor.author	Reis, H	en
dc.contributor.author	Papadopoulos, MG	en
dc.date.accessioned	2014-03-01T02:08:33Z
dc.date.available	2014-03-01T02:08:33Z
dc.date.issued	2012	en
dc.identifier.issn	15499596	en
dc.identifier.uri	https://dspace.lib.ntua.gr/xmlui/handle/123456789/29663
dc.subject.other	Bi-layer	en
dc.subject.other	Binding cavity	en
dc.subject.other	Biological actions	en
dc.subject.other	Computational studies	en
dc.subject.other	HIV-1 protease	en
dc.subject.other	Human immunodeficiency virus type-1	en
dc.subject.other	Non-polar	en
dc.subject.other	Poisson Boltzmann surface areas (PBSA)	en
dc.subject.other	Potent drugs	en
dc.subject.other	Quantum mechanical	en
dc.subject.other	Stable structures	en
dc.subject.other	Van Der Waals interactions	en
dc.subject.other	Water molecule	en
dc.subject.other	Binding energy	en
dc.subject.other	Fullerenes	en
dc.subject.other	Hydrogen bonds	en
dc.subject.other	Ligands	en
dc.subject.other	Molecular dynamics	en
dc.subject.other	Molecules	en
dc.subject.other	Van der Waals forces	en
dc.subject.other	Viruses	en
dc.subject.other	Drug interactions	en
dc.title	Computational studies of darunavir into HIV-1 protease and DMPC bilayer: Necessary conditions for effective binding and the role of the flaps	en
heal.type	journalArticle	en
heal.identifier.primary	10.1021/ci300014z	en
heal.identifier.secondary	http://dx.doi.org/10.1021/ci300014z	en
heal.publicationDate	2012	en
heal.abstract	Human immunodeficiency virus type 1 protease (HIV-1 PR) is one of the main targets toward AIDS therapy. We have selected the potent drug darunavir and a weak inhibitor (fullerene analog) as HIV-1 PR substrates to compare protease's conformational features upon binding. Molecular dynamics (MD), molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), and quantum-mechanical (QM) calculations indicated the importance of the stability of HIV-1 PR flaps toward effective binding: a weak inhibitor may induce flexibility to the flaps, which convert between closed and semiopen states. A water molecule in the darunavir-HIV-1 PR complex bridged the two flap tips of the protease through hydrogen bonding (HB) interactions in a stable structure, a feature that was not observed for the fullerene-HIV-1 PR complex. Additionally, despite that van der Waals interactions and nonpolar contribution to solvation favored permanent fullerene entrapment into the cavity, these interactions alone were not sufficient for effective binding; enhanced electrostatic interactions as observed in the darunavir-complex were the crucial component of the binding energy. An alternative pathway to the usual way of a ligand to access the cavity was also observed for both compounds. Each ligand entered the binding cavity through an opening between the one flap of the protease and a neighboring loop. This suggested that access to the cavity is not necessarily regulated by flap opening. Darunavir exerts its biological action inside the cell, after crossing the membrane barrier. Thus, we also initiated a study on the interactions between darunavir and the DMPC bilayer to reveal that the drug was accommodated inside the bilayer in conformations that resembled its structure into HIV-1 PR, being stabilized via HBs with the lipids and water molecules. © 2012 American Chemical Society.	en
heal.journalName	Journal of Chemical Information and Modeling	en
dc.identifier.doi	10.1021/ci300014z	en
dc.identifier.volume	52	en
dc.identifier.issue	6	en
dc.identifier.spage	1542	en
dc.identifier.epage	1558	en