Rational Design and Optimization of Novel PDE5 Inhibitors for Targeted Colorectal Cancer Therapy: An In Silico Approach.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths globally. Current treatment options including chemotherapy and targeted therapies face challenges such as resistance and toxicity. Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5) has emerged as a promising target for CRC therapy due to its role in regulating cellular processes like proliferation and apoptosis. This study focuses on the in silico design of a novel PDE5 inhibitor MS01 derived from the lead compound exisulind which has shown apoptotic effects but failed due to hepatotoxicity. Using Schrödinger's Induced Fit Docking (IFD) and molecular dynamic simulations, MS01 was designed to enhance binding affinity and reduce toxicity. The docking studies showed that MS01 exhibits stronger interactions with key PDE5 residues, particularly Gln817 and Phe820. ADMET predictions indicate favorable pharmacokinetic profiles, with reduced risk of drug-drug interactions and improved bioavailability. Toxicity assessments revealed that MS01 and its analogs have moderate toxicity, with MS20 and MS21 demonstrating lower hepatotoxicity compared to exisulind. These findings suggest that MS01 has the potential to be a more effective and safer PDE5 inhibitor for CRC treatment pending further experimental validation.