ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

In silico approach for fighting human immunodeficiency virus: a drug repurposing strategy

Luminita Crisan and Daniela Istrate

“Coriolan Dragulescu” Institute of Chemistry, Timisoara, Romania

E-mail: lumi_crisan@acad-icht.tm.edu.ro

Received: 26 February 2024  Accepted: 24 September 2024

Abstract:

The global spread of the human immunodeficiency virus (HIV) constitutes a significant threat to human health, focusing the important task for today’s scientific community to explore anti-HIV drug design and address the urgent need for drug repurposing strategies given the challenge of HIV drug resistance. In this study, a library of 4099 marketed drugs was computationally evaluated using similarity search, e-pharmacophore, molecular docking, binding free energy, pharmacokinetic estimation, antiviral activity prediction analysis, hierarchical clustering, molecular electrostatic potential, and crystal structures of the HIV-1 reverse transcriptase (RT) enzyme. Reliable pharmacophore models were obtained with AUC values of 0.858 (± 0.015) for Pharm-1 and 0.864 (± 0.016) for Pharm-2. Similarly, the molecular docking showed AUC values of 0.835 (± 0.024) for SP glide and 0.819 (± 0.021) for XP glide. The multi-step computational process initially identified 120 drugs through similarity analysis, followed by 1489 drugs selected by Pharm-1 and 1945 displayed by Pharm-2. Finally, after molecular docking and binding free energy analysis four potential candidates (procaterol, pravastatin, pergolide, and ropinirole) with promising inhibitory effects on HIV-1 RT (pIC50 values of 5.714, 5.888, 6.269, and 6.383 and predicted inhibition of 46.58%, 51.87%, 51.70%, and 51.61%, respectively) were selected. This protocol seems to provide a viable solution for exploring marketed drugs and their potential repositioning for HIV-1 RT, and can be expanded to investigate different protein targets, thereby identifying novel candidates for experimental testing. Further validation through experimental studies can pinpoint the bioactivity of selected drugs, facilitating their potential application in the management of HIV disease.

Graphical abstract

Keywords: HIV-1 RT; e-pharmacophore; Molecular docking; MM-GBSA; Antiviral activity prediction; Hierarchical clustering

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-024-03789-5

Chemical Papers 79 (1) 417–435 (2025)