Background and aims. Cyclin-dependent Kinase-5 (CDK-5) is a phosphorylating enzyme known for its function in neuronal disorders and cell cycle regulation. Benzofuropyridine (BFP) is a class of heteroaromatic molecules with reported inhibition against CDK-5. Known structural derivatives of the compound remain scarce, prompting the use of computational methods in improving the structural framework of the BFP, to produce more potent derivatives.
Methods. Herein, three derivatization strategies for the diversification of the BFP core moiety were planned. The series namely: BX-1-1 (45 analogs), B1-X-1 (33 analogs), and B1-1-X (26 analogs) were prepared and drawn using known soft wares, was subjected to molecular docking study, and the drug-likeliness prediction was performed using SwissADME.
Results. Results showed that among the three series, the BX-1-1, focusing on the 2O-position of the BFP, postured optimum potential for structural diversification as inhibitors, with the B29-1-1 analog having the highest binding affinity of -10.7 kcal/mol. Interestingly, the B1-X-1 series was identified to be the least likely plan to produce more improved analogs. Key residues such as Phe80, Cys83 and Lys33 with their specific interactions to the BFP representative analogs, were identified. The drug-like properties assessment demonstrated the potential of the analogs for drug development, with their good bioavailability score and optimum synthetic accessibility.
Conclusion/Discussion. This study offered a more cohesive understanding of the relationship between the substitution of the Benzofuropyridine and its improved biological therapeutic functions. Altogether, it provided fundamental information on the medicinal chemistry of the BFP, its synthetic derivatization, and the production of potent and more selective drugs, highlighting the imminent possibility of using computer algorithms for future drug design and development.