VOLUME 19 NUMBER 2 (July to December 2026)

In silico optimization of the Benzofuropyridine core structure as CDK-5 inhibitor

Cyclin-dependent kinase-5 (CDK-5) is a phosphorylating enzyme known for its function in neuronal disorders. Benzofuropyridines (BFP) are a class of heteroaromatic molecules that inhibit CDK-5. Known structural derivatives of this compound remain scarce, prompting the use of computational methods to produce more potent derivatives. In this study, three derivatization strategies were employed to design the BX-1-1 (45 analogs), B1-X-1 (33 analogs), and B1-1-X (26 analogs) series. These analogs were evaluated using computational tools such as molecular docking, SwissADME and molecular dynamics simulations. Results showed that the BX-1-1 series, focusing on the functionalization of the 2-O position of BFP, showed the greatest potential for structural diversification as inhibitors, with the B29-1-1 analog having the highest binding energy of -10.7 kcal/mol. Key residues, such as Phe80, Cys83, and Lys33, with their specific interactions with the 9 BFP representative analogs were identified. The drug-like properties of the compounds were assessed, and the results demonstrated the potential of the analogs for drug development, with good bioavailability scores and optimum synthetic accessibility. Moreover, B1-11-1 and B1-1-18 (binding energies: -9.5 and -10.2 kcal/mol respectively) are two lead compounds having high affinity for CDK-5 and good potential to permeate the Blood-Brain Barrier. The CDK-5 enzyme alone remained stable, but the B29-1-1 ligand-protein complex exhibited limited stability over the 100-nanosecond molecular dynamics simulation. Overall, this work provided valuable insights into the future design of BFP as CDK-5 inhibitors using computational tools.