Computational Discovery of Dual Inhibitors for HIV-1 Therapy

İbişoğlu M. S., Güler H. İ.

VII. International Enzyme and Bioprocess Days, Trabzon, Türkiye, 26 - 28 Ağustos 2026, ss.69, (Özet Bildiri)

  • Yayın Türü: Bildiri / Özet Bildiri
  • Basıldığı Şehir: Trabzon
  • Basıldığı Ülke: Türkiye
  • Sayfa Sayıları: ss.69
  • Karadeniz Teknik Üniversitesi Adresli: Evet

Özet

Human immunodeficiency virus type 1 (HIV-1) remains a major global health challenge due to increasing drug resistance and the continuous need for more effective therapeutic strategies. Simultaneous targeting of multiple viral proteins has emerged as a promising strategy to enhance antiviral efficacy while reducing the likelihood of resistance development. In this study, pharmacophore models were generated for two essential HIV-1 enzymes, Reverse Transcriptase and Protease, using nevirapine and darunavir as reference drugs, respectively. Pharmacophore-based virtual screening was performed using the Pharmit platform against approximately 103.3 million compounds in the PubChem database, resulting in the identification of 86 molecules that satisfied the pharmacophore requirements of both targets. The selected compounds were subsequently evaluated using molecular docking, molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and ADMET analyses to investigate their binding affinity, complex stability, and pharmacokinetic properties. Molecular docking identified 20 compounds with more favorable binding profiles than the reference drugs against both HIV-1 targets. ADMET analysis highlighted PubChem-2969176 and PubChem-97261679 as the most promising dual-target inhibitor candidates. MD simulations confirmed the stability of the protein–ligand complexes, while MM/PBSA analysis revealed that PubChem-2969176 exhibited stronger binding free energies toward HIV-1 Protease and HIV-1 Reverse Transcriptase (ΔG = −37.08 and −55.66 kcal/mol, respectively) than PubChem-97261679. Considering both binding affinity and ADMET characteristics, PubChem-2969176 emerged as the most promising balanced dual inhibitor candidate. Overall, this integrated pharmacophore- and structure-based computational workflow identified PubChem-2969176 as a promising lead compound for the future development of dual-target anti-HIV therapeutics.