Binding energy analysis for wild-type and Y181C mutant HIV-1 RT/8-Cl TIBO complex structures: quantum chemical...

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• The human immunodeficiency virus (HIV) reverse transcriptase is a key target for antiviral therapies.
• Resistance mutations, such as Y181C, can reduce the efficacy of existing drugs.
• Understanding inhibitor binding at a molecular level is crucial for developing new drugs.

Purpose of the Study:

• To compare the binding energies of the 8-Cl TIBO inhibitor in wild-type HIV reverse transcriptase and a Y181C mutant.
• To elucidate the energetic contributions of the Y181C mutation to inhibitor binding.
• To provide atomistic insights into drug resistance mechanisms.

Main Methods:

• ONIOM (Our Own N-layered Integrated molecular Orbital and molecular Mechanics) calculations were employed.
• Two-layered and three-layered ONIOM approaches were utilized.
• Various quantum mechanical methods (MP2/6-31G(d), B3LYP/6-31G(d,p), PM3) were combined within the ONIOM framework.

Main Results:

• The Y181C mutation was found to decrease the binding affinity and stability of the 8-Cl TIBO inhibitor by approximately 8-9 kcal/mol.
• Energetic components of interaction and deformation energies were analyzed.
• Atomistic-level interaction energies between the inhibitor and surrounding residues were calculated for both wild-type and mutant enzymes.

Conclusions:

• The Y181C mutation significantly impairs the binding of the 8-Cl TIBO inhibitor to HIV reverse transcriptase.
• Computational modeling provides valuable insights into the molecular basis of drug resistance.
• These findings can inform the design of novel inhibitors effective against resistant viral strains.