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.
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 (ΔG(pred) = -9.1 kcal mol(-1) for canagliflozin-renin; K(i,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 (K(i,exp)= 76.5 nM) and renin (K(i,pred)= 261 nM), respectively. Importantly, a high correlation was observed between experimental and predicted binding energies (r(2) = 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.
authors.affiliation: Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vas. Constantinou Avenue, Athens 11635, Greece.
authors.forename: Haralambos
authors.initials: H
authors.lastname: Tzoupis
authors.forename: Georgios
authors.initials: G
authors.lastname: Leonis
authors.forename: Grigorios
authors.initials: G
authors.lastname: Megariotis
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.forename: Manthos G
authors.initials: MG
authors.lastname: Papadopoulos
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D003920:Diabetes Mellitus / Q000188:drug therapy*; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D006860:Hydrogen Bonding; D006973:Hypertension / Q000188:drug therapy*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D012083:Renin / Q000737:chemistry / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013816:Thermodynamics; D000092502:Renin Inhibitors
chemical_list: D016333:HIV Protease; D017320:HIV Protease Inhibitors; D012083:Renin; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000092502:Renin Inhibitors