In Silico and In Vitro Evaluation of Bis-Imidazole Derivatives as Potential HIV-1 Reverse Transcriptase Inhibitors

Altuntaş E., Ünver Y., Güler H. İ.

III. International Apitherapy and Nature Congress, Baku, Azerbaycan, 21 - 23 Kasım 2025, ss.265, (Özet Bildiri)

  • Yayın Türü: Bildiri / Özet Bildiri
  • Basıldığı Şehir: Baku
  • Basıldığı Ülke: Azerbaycan
  • Sayfa Sayıları: ss.265
  • Karadeniz Teknik Üniversitesi Adresli: Evet

Özet

The discovery of novel HIV-1 reverse transcriptase (RT) inhibitors remains crucial due to the continuous emergence of drug resistance against current antiretroviral agents. In this study, three bis-imidazole derivatives (3e, 3f, and 3g) were evaluated for their inhibitory potential against HIV-1 RT using a combined in silico and in vitro strategy. Molecular docking simulations (PDB ID: 3T19, AutoDock 4.2.6) revealed distinct binding profiles. Compound 3e exhibited the most favorable binding energy (−9.18 kcal/mol) and demonstrated potent inhibition (Ki = 186.36 nM), despite the absence of hydrogen bonds, with stabilization mediated primarily through van der Waals interactions involving residues such as His235, Phe227, and Tyr319. Compound 3f showed strong inhibition (Ki = 1.96 μM), supported by four hydrogen bonds and extensive interactions with Asp117, Glu138, Tyr181, and Pro95, highlighting its stable accommodation within the RT binding pocket. Compound 3g displayed moderate inhibition (Ki = 8.59 μM) with three hydrogen bonds and interactions involving Tyr188, Trp229, and Lys101. For comparison, the reference inhibitor nevirapine (−9.53 kcal/mol, Ki = 103.97 μM) formed a single hydrogen bond and engaged residues such as Tyr318, His235, and Phe227.
Experimental validation through a colorimetric ELISA-based RT inhibition assay confirmed the computational predictions. Among the tested compounds, 3f exhibited the most potent dose-dependent inhibition in vitro, whereas docking suggested compound 3e as the most favorable binder. Together, these findings reveal bis-imidazole derivatives, particularly 3e and 3f, as promising scaffolds for the rational design of next-generation HIV-1 RT inhibitors, warranting further optimization and preclinical exploration.