Dual inhibitors for aspartic proteases HIV-1 PR and renin: Advancements in AIDS-hypertension-diabetes linkage via Molecular dynamics, inhibition assays, and binding free energy calculations

Tzoupis, H; Leonis, G; Megariotis, G; Supuran, CT; Mavromoustakos, T; Papadopoulos, MG

dc.contributor.author	Tzoupis, H	en
dc.contributor.author	Leonis, G	en
dc.contributor.author	Megariotis, G	en
dc.contributor.author	Supuran, CT	en
dc.contributor.author	Mavromoustakos, T	en
dc.contributor.author	Papadopoulos, MG	en
dc.date.accessioned	2014-03-01T02:08:41Z
dc.date.available	2014-03-01T02:08:41Z
dc.date.issued	2012	en
dc.identifier.issn	00222623	en
dc.identifier.uri	https://dspace.lib.ntua.gr/xmlui/handle/123456789/29706
dc.subject.other	aliskiren	en
dc.subject.other	canagliflozin	en
dc.subject.other	darunavir	en
dc.subject.other	Human immunodeficiency virus proteinase	en
dc.subject.other	renin	en
dc.subject.other	acquired immune deficiency syndrome	en
dc.subject.other	article	en
dc.subject.other	binding affinity	en
dc.subject.other	controlled study	en
dc.subject.other	diabetes mellitus	en
dc.subject.other	drug binding	en
dc.subject.other	drug mechanism	en
dc.subject.other	drug structure	en
dc.subject.other	enzyme inhibition	en
dc.subject.other	enzyme structure	en
dc.subject.other	hypertension	en
dc.subject.other	molecular docking	en
dc.subject.other	molecular dynamics	en
dc.subject.other	prediction	en
dc.subject.other	Acquired Immunodeficiency Syndrome	en
dc.subject.other	Diabetes Mellitus	en
dc.subject.other	HIV Protease	en
dc.subject.other	HIV Protease Inhibitors	en
dc.subject.other	HIV-1	en
dc.subject.other	Humans	en
dc.subject.other	Hydrogen Bonding	en
dc.subject.other	Hypertension	en
dc.subject.other	Molecular Dynamics Simulation	en
dc.subject.other	Protein Binding	en
dc.subject.other	Protein Conformation	en
dc.subject.other	Renin	en
dc.subject.other	Sodium-Glucose Transporter 2	en
dc.subject.other	Thermodynamics	en
dc.title	Dual inhibitors for aspartic proteases HIV-1 PR and renin: Advancements in AIDS-hypertension-diabetes linkage via Molecular dynamics, inhibition assays, and binding free energy calculations	en
heal.type	journalArticle	en
heal.identifier.primary	10.1021/jm300180r	en
heal.identifier.secondary	http://dx.doi.org/10.1021/jm300180r	en
heal.publicationDate	2012	en
heal.abstract	Human immunodeficiency virus type 1 protease (HIV-1 PR) and renin are primary targets toward AIDS and hypertension therapies, respectively. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free-energy calculations and inhibition assays for canagliflozin, an antidiabetic agent verified its effective binding to both proteins (ΔGpred = 9.1 kcal mol-1 for canagliflozin-renin; Ki,exp= 628 nM for canagliflozin-HIV-1 PR). Moreover, drugs aliskiren (a renin inhibitor) and darunavir (an HIV-1 PR inhibitor) showed high affinity for HIV-1 PR (Ki,exp= 76.5 nM) and renin (Ki,pred= 261 nM), respectively. Importantly, a high correlation was observed between experimental and predicted binding energies (r2 = 0.92). This study suggests that canagliflozin, aliskiren, and darunavir may induce profound effects toward dual HIV-1 PR and renin inhibition. Since patients on highly active antiretroviral therapy (HAART) have a high risk of developing hypertension and diabetes, aliskiren-based or canagliflozin-based drug design against HIV-1 PR may eliminate these side-effects and also facilitate AIDS therapy. © 2012 American Chemical Society.	en
heal.journalName	Journal of Medicinal Chemistry	en
dc.identifier.doi	10.1021/jm300180r	en
dc.identifier.volume	55	en
dc.identifier.issue	12	en
dc.identifier.spage	5784	en
dc.identifier.epage	5796	en