3D QSAR modeling study on 7-aminofuro [2,3-c] pyridine derivatives as TAK1 inhibitors using CoMFA and COMSIA

Abstract TAK1 is a member of the MAPKKK family, and it is one of the key molecules in inflammatory signaling pathways. It is an interesting drug target recently because of its role in many signaling pathways and various cellular processes. In the present study, a series of recently published 7-aminofuro [2,3-c] pyridine derivatives were taken as TAK1 antagonists, and 3D QSAR study was performed. A reasonable CoMFA (q2 = 0.690 NOC = 6, r2 = 0.946) and COMSIA (q2 = 0.676, NOC = 5, r2 = 0.904) models were developed. All the developed models were validated using external validation test set, leave five out, bootstrapping, progressive samplings, and rm2 metrics. Both the models exhibited acceptable values on all validation techniques and, hence, was considered to be robust and predictive. Furthermore, the contour map analysis of CoMFA and COMSIA models exposed important understandings in the substituents to increase the potency of the compounds. Small negative substitutions at R1 position of five-membered ring found to increase the activity. Similarly, hydrophobic substitution and hydrogen bond acceptor group at the R1 position of the five-membered ring could increase the activity. Avoiding bulky substitution and hydrogen bond acceptor group near the phenyl ring at R1 position and R8 would help in increasing the potency of the compounds. Our finding could be used to design a more potent derivative of TAK1 inhibitors.Graphical abstract

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