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

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.