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

Area of Science:

• Oncology
• Pharmacology
• Computational Chemistry

Background:

• Colorectal cancer (CRC) remains a leading global cause of cancer mortality.
• Current CRC treatments like chemotherapy and targeted therapies are limited by drug resistance and toxicity.
• Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5) is a promising therapeutic target for CRC due to its role in cell proliferation and apoptosis.

Purpose of the Study:

• To design a novel PDE5 inhibitor, MS01, based on the exisulind scaffold.
• To enhance binding affinity and reduce toxicity of PDE5 inhibitors for colorectal cancer therapy.
• To computationally evaluate the potential of MS01 as a safer and more effective CRC treatment.

Main Methods:

• In silico design utilizing Schrödinger's Induced Fit Docking (IFD).
• Molecular dynamic simulations to assess binding interactions and stability.
• ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) predictions for pharmacokinetic profiling.
• In silico toxicity assessments, including hepatotoxicity evaluation.

Main Results:

• MS01 demonstrated enhanced binding interactions with key PDE5 residues (Gln817, Phe820) compared to the lead compound.
• ADMET predictions suggest favorable pharmacokinetic properties, including improved bioavailability and reduced drug-drug interaction risk.
• MS01 and its analogs (MS20, MS21) exhibited moderate toxicity with notably lower predicted hepatotoxicity than exisulind.

Conclusions:

• The in silico designed PDE5 inhibitor MS01 shows significant potential as a more effective and safer therapeutic agent for colorectal cancer.
• MS01's favorable predicted pharmacokinetic and toxicity profiles warrant further experimental investigation.
• This study highlights the utility of computational methods in designing novel anticancer drug candidates with improved safety profiles.