Structural, QSAR, machine learning and molecular docking studies of 5-thiophen-2-yl pyrazole derivatives as potent and selective cannabinoid-1 receptor antagonists

Abstract

We performed a structural study followed by theoretical analysis of the chemical descriptors and biological activity of a series of 5-thiophen-2-yl pyrazole derivatives as potent and selective cannabinoid-1 (CB1) receptor antagonists. The structures and molecular properties of these compounds were obtained using a DFT-D3 (B3LYP(+D3)) approach in conjunction with the 6-311G(d,p) basis set. We also derived the physicochemical properties and the binding of these derivatives interacting with the CB1 receptor. Computations show that all of them present the same molecular subunit structure, miming that of rimonabant, an efficient CB1 antagonist. The 3D structure of this subunit, important for the interaction with the receptor, is strongly influenced by long-range interactions. Moreover, we derived a QSAR equation to model the biological activity of this series. Close agreement with experimental data is found. Moreover, molecular docking studies were carried out between the most active compound and both the inactive and active states of the CB1 receptor. Results reveal high affinity between this compound and the inactive CB1 conformation, mainly governed by van der Waals forces. In conclusion, our work suggests that this compound could be a novel efficient inhibitor of CB1.