A Deep Dive into PDE5 Inhibition: Innovative Discoveries via Virtual Screening

Abstract

Background: PDE5 inhibitors have had a surge in popularity over the last decade owing to their efficacy in the treatment of erectile dysfunction, coronary vasculopathy, and pulmonary arterial hypertension. These inhibitors exhibit competitive binding with phosphodiesterase type 5 and inhibit the hydrolysis of cyclic guanosine monophosphate, hence elevating the levels of cGMP in smooth muscle cells and prolonging the duration of an erection. However, due to production costs and side effects, further research is needed to discover new PDE5 inhibitors. background: The field of PDE5 inhibitors has risen in popularity in the past decade because of the success of PDE5 inhibitors in treating erectile dysfunction. Due to the structural identity with cGMP; PDE5 inhibitors competitively bind with PDE5 and limit cGMP hydrolysis, which raises the cGMP level in smooth muscle cells and lengthens the duration of an erection. PDE5 inhibitors were also found to be beneficial for coronary vasculopathy, pulmonary arterial hypertension, and benign prostatic hyperplasia. But, due to the expensive cost of production and unwanted side effects, it is necessary to explore the possibility of the discovery of new PDE5 inhibitors. Objective: The study aimed to identify potent PDE5 inhibitors by employing the extensive application of computer-aided drug design. objective: To identify potent PDE5 inhibitors by employing the extensive application of computer-aided drug design. Method: Three different databases, named Million Molecules Database, Natural Product Database, and NCI Database, have been screened, which has been followed by filtering based on various druglikeness rules, docking, ADME, toxicity, consensus molecular docking, and 100 ns molecular dynamics simulation. method: Three different databases named Million Molecules Database, Natural Product Database, and NCI Database has been screened followed by filtering based on various drug-likeness such as Lipinski rule of five, Ghose rule, Veber rule, and Muegge rule, docking, ADME, toxicity, consensus molecular docking, and 100 ns Molecular dynamics simulation Results: Three compounds (ZINC05351336, ZINC12030898, and ZINC17949426) have exhibited stable-binding characteristics at the active site of PDE5, demonstrating a robust binding affinity. These molecules have been found to possess drug-like capabilities, effective ADME features, low toxicity, and high stability. Conclusion: The study has delved into the realm of PDE5 inhibitors, which have been found to be effective in treating erectile dysfunction, but high production costs and side effects necessitate new ones. Through computer-aided drug design and screening, three compounds have been identified with promising binding characteristics, drug-appropriate properties, effective ADME profiles, minimal toxicity, and stability, making them potential candidates for future PDE5 inhibitors