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.
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Tzoupis H, Leonis G, Megariotis G, Supuran CT, Mavromoustakos T, Papadopoulos MG
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.
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- 22621689 [ View in PubMed]
- 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 (DeltaG(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.