Structure-Based Repurposing of Clinically Approved Compounds for PDE-5 Inhibition: Integrative Computational and Pharmacokinetic Evaluation

Authors

Albashir Tahir, Department of Pharmacology, Faculty of Basic Medical Sciences, Sa’adu Zungur University, Bauchi State, NigeriaFollow
Yasir Idris Saleh, Department of Biochemistry, Faculty of Sciences, Sa’adu Zungur University, Bauchi State, NigeriaFollow
Ibrahim Khaleel Muazu, Department of Pharmaceutical Technology, Federal Polytechnic Damaturu, Yobe State, NigeriaFollow

Abstract

Background: Phosphodiesterase-5 (PDE-5) regulates intracellular cyclic guanosine monophosphate (cGMP) levels, modulating vascular smooth muscle tone. Sildenafil, a well-established PDE-5 inhibitor, is effective for erectile dysfunction and pulmonary hypertension but causes dose-dependent adverse effects. Identifying alternative scaffolds with comparable efficacy and improved safety remains a pharmacological priority.

Methods: A ligand-based virtual screening of the DrugBank database was performed using sildenafil as a reference. Compounds exhibiting ≥60% structural and electrostatic similarity were docked into the PDE-5 catalytic domain (PDB ID: 2h42) using Glide XP in the Schrödinger Suite. Top-scoring ligands were assessed for physicochemical, pharmacokinetic (ADMET), and toxicity parameters using SwissADME and ProTox-II tools.

Results: Twenty-four FDA-approved drugs showed ≥60% similarity to sildenafil. Sildenafil exhibited the strongest binding affinity (–11.399 kcal/mol), followed by topotecan (–9.537 kcal/mol) and irinotecan (–8.542 kcal/mol). Both camptothecin derivatives formed hydrogen bonds and π–π stacking with key PDE-5 residues (Gln817, Ser663, Phe820). ADMET predictions indicated high gastrointestinal absorption and moderate oral bioavailability (0.55) for all compounds. Toxicity modeling classified sildenafil as low-risk (LD₅₀ = 1000 mg/kg) and topotecan/irinotecan as moderately toxic, consistent with their anticancer pharmacology.

Conclusion: Topotecan and irinotecan demonstrated strong PDE-5 binding and favorable pharmacokinetic profiles, identifying them as promising scaffolds for selective PDE-5 inhibitor development. Despite moderate toxicity, structural optimization could improve safety, highlighting the value of in-silico repurposing in accelerating discovery of novel PDE-5-targeted therapeutics.

Recommended Citation

Tahir, Albashir; Saleh, Yasir Idris; and Muazu, Ibrahim Khaleel (2025) "Structure-Based Repurposing of Clinically Approved Compounds for PDE-5 Inhibition: Integrative Computational and Pharmacokinetic Evaluation," Al-Mustaqbal Journal of Pharmaceutical and Medical Sciences: Vol. 3 : Iss. 3 , Article 5.
Available at: https://doi.org/10.62846/3006-5909.1036