Rational scaffold discovery for HIV-1 reverse transcriptase inhibitors via integrated in silico approaches

Area of Science:

• Computational chemistry and drug discovery
• Virology and infectious diseases
• Medicinal chemistry

Background:

• Current non-nucleoside reverse transcriptase inhibitors (NNRTIs) for Human Immunodeficiency Virus-1 (HIV-1) treatment face challenges due to drug-induced liver toxicity.
• HIV-1 Reverse Transcriptase (RT) remains a critical target for antiviral therapies.

Purpose of the Study:

• To identify novel NNRTI scaffolds with enhanced safety and efficacy profiles using an integrated in silico approach.
• To evaluate potential hepatotoxicity and binding stability of candidate NNRTIs.

Main Methods:

• Employed similarity-based virtual screening, molecular docking, molecular dynamics simulations, and MM-PBSA calculations.
• Utilized ADMET filtering for hepatotoxicity prediction and molecular descriptor analysis for electronic properties.
• Assessed binding stability through RMSD, hydrogen bond analysis, and protein backbone fluctuations.

Main Results:

• ZINC000066352010 demonstrated reduced predicted hepatotoxicity compared to existing NNRTIs.
• Exhibited stable binding to the HIV-1 RT NNRTI pocket, with strong hydrogen bonding and hydrophobic interactions.
• Achieved a favorable binding energy of -47.90 Kcal/mol and optimal electronic properties (HOMO-LUMO gap, electrophilicity index).

Conclusions:

• ZINC000066352010 is a promising NNRTI candidate with predicted improved safety and electronic stability.
• The computational strategy successfully identified a potent and potentially safer alternative to current HIV-1 RT inhibitors.
• Further experimental validation is warranted to confirm the therapeutic potential of ZINC000066352010.