ONIOM DFT/PM3 calculations on the interaction between dapivirine and HIV-1 reverse transcriptase, a theoretical study

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Human immunodeficiency virus type 1 (HIV-1) remains a global health challenge.
• Antiretroviral therapy, including non-nucleoside reverse transcriptase inhibitors (NNRTIs), is critical for HIV management.
• Understanding drug-target interactions at a molecular level is essential for developing more effective treatments.

Purpose of the Study:

• To investigate the molecular interactions between the anti-HIV drug dapivirine and the HIV-1 reverse transcriptase (RT) binding site.
• To elucidate the key binding forces responsible for the stability of the dapivirine-NNIBP complex.
• To computationally predict the binding energy of the dapivirine-HIV-1 RT complex.

Main Methods:

• Theoretical investigations using ONIOM2 (B3LYP/6-31G (d,p): PM3) and B3LYP/6-31G (d,p) computational methods.
• Analysis of hydrogen bonding, π-π stacking, and H…π interactions.
• Calculation of binding energy for the optimized complex structure.

Main Results:

• Dapivirine forms two key hydrogen bonds with Lys101 residue in the HIV-1 RT binding site.
• Strong π-π stacking or H…π interactions were observed between dapivirine and Tyr181 and Tyr188 residues.
• The calculated binding energy for the BBF optimized structure of the complex was -18.20 kcal/mol, indicating favorable binding.

Conclusions:

• The identified hydrogen bonds and π-π/H…π interactions are critical for stabilizing the dapivirine-NNIBP complex.
• These findings provide valuable molecular insights into the mechanism of action of dapivirine.
• The computational results support dapivirine's role as an effective HIV-1 RT inhibitor and inform future drug design strategies.