Diketoacid HIV-1 integrase inhibitors: An ab initio study

Area of Science:

• Computational Chemistry
• Medicinal Chemistry
• Molecular Modeling

Background:

• HIV-1 integrase inhibitors are crucial for antiretroviral therapy.
• Understanding the tautomeric forms of these inhibitors is essential for drug design.
• 5-ClTEP and L-731,988 are representative arene-substituted diketoacid inhibitors.

Purpose of the Study:

• To investigate the stable tautomeric forms of 5-ClTEP and L-731,988.
• To compare the stability of diketo and enol tautomers using computational methods.
• To determine the preferred conformation for HIV-1 integrase inhibition.

Main Methods:

• Density Functional Theory (DFT) calculations using B3LYP functional.
• Various basis sets including 6-31G*, 6-31G(d,p), and 6-31+G(d,p).
• Conductor-like screening model for solvation effects.
• MP2/6-31G* optimization for 5-ClTEP.

Main Results:

• Trans diketo conformations are more stable than cis conformers in DFT calculations.
• Two distinct trans diketo structures were identified with minimal energy difference.
• Enol forms were found to be more stable than diketo tautomers and possess equal free energy.
• DFT results favor enol tautomers, consistent with experimental observations.

Conclusions:

• The B3LYP method correctly predicts the prevalence of enol tautomers for these inhibitors.
• Enol tautomers, potentially existing in a delocalized transition state, are likely the active forms.
• Computational findings support experimental data, aiding in the rational design of HIV-1 integrase inhibitors.