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

J Med Chem. 2012 Jun 28;55(12):5784-96. doi: 10.1021/jm300180r. Epub 2012 Jun 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acquired Immunodeficiency Syndrome / drug therapy*
  • Diabetes Mellitus / drug therapy*
  • HIV Protease / chemistry
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / metabolism
  • HIV Protease Inhibitors / pharmacology
  • HIV Protease Inhibitors / therapeutic use
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Hydrogen Bonding
  • Hypertension / drug therapy*
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Conformation
  • Renin / antagonists & inhibitors*
  • Renin / chemistry
  • Renin / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors
  • Thermodynamics

Substances

  • HIV Protease Inhibitors
  • Sodium-Glucose Transporter 2 Inhibitors
  • HIV Protease
  • Renin