Oladeji Samson Marvellous, Conteh Deborah Ngozi, Bello Lukman Abidemi, Adegboyega Abayomi Emmanuel, Shokunbi Oluwatosin Sarah
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Department of Medicine and Surgery, University of Ilorin, P.M.B, Ilorin 1515, Nigeria.
Int J Mol Sci. 2025 Feb 24;26(5):1937. doi: 10.3390/ijms26051937.
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.
结直肠癌（CRC）是全球癌症相关死亡的主要原因之一。目前的治疗选择，包括化疗和靶向治疗，面临着诸如耐药性和毒性等挑战。环磷酸鸟苷（cGMP）特异性磷酸二酯酶5（PDE5）因其在调节细胞增殖和凋亡等过程中的作用，已成为CRC治疗的一个有前景的靶点。本研究聚焦于一种新型PDE5抑制剂MS01的计算机辅助设计，该抑制剂源自先导化合物依西美坦，依西美坦已显示出凋亡作用，但因肝毒性而失败。利用薛定谔的诱导契合对接（IFD）和分子动力学模拟，设计MS01以增强结合亲和力并降低毒性。对接研究表明，MS01与关键的PDE5残基，特别是Gln817和Phe820，表现出更强的相互作用。ADMET预测表明其具有良好的药代动力学特征，药物相互作用风险降低，生物利用度提高。毒性评估显示，MS01及其类似物具有中等毒性，与依西美坦相比，MS20和MS21的肝毒性较低。这些发现表明，在进一步的实验验证之前，MS01有潜力成为一种更有效、更安全的用于CRC治疗的PDE5抑制剂。
