Structure determinants of indolin-2-on-3-spirothiazolidinones as MptpB inhibitors: An in silico study

Abstract

Tuberculosis caused by Mycobacterium tuberculosis (Mtb), is a major factor of death around the world. Mtb protein tyrosine phosphatase B (MptpB), a virulent phosphatase encoded by Mtb, is a potential target for the treatment of tuberculosis. To explore the structure features of 134 indolin-2-on-3-spirothiazolidinones as MptpB inhibitors, in this work, a set of ligand- and receptor-based 3D-QSAR studies were, for the first time, carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques. Splitting of the training and test sets was constructed by Kohonen's self-organizing map algorithm. Additionally, to profile the possible binding modes of these inhibitors, molecule docking and molecular dynamics (MD) simulations were performed as well. The optimal QSAR models built on both ligand- and receptor-based alignments exhibit proper reliabilities and predictive abilities as illustrated by their statistical results that for ligand-based alignment CoMFA and CoMSIA models obtain Q² = 0.662, R_ncv² = 0.799, R_pre² = 0.757, and Q² = 0.736, R_ncv² = 0.847, R_pre² = 0.866; whereas for docking-based one achieve Q² = 0.536, R_ncv² = 0.894, R_pre² = 0.823, and Q² = 0.498, R_ncv² = 0.812, R_pre² = 0.833, respectively. Furthermore, the contours generated from these models are well consistent with the docking and MD results we performed. Our findings are: (1) Indolin-2-on-3-spirothiazolidinones may bind to the MptpB with a “cockhorse” conformation, which is stabilized by eight H-bonds formed with the surrounding residues (Arg166, Cys160, Ala162, Lys164, His94 and Glu129), one cation–π interaction with the side chain of Arg166 and two hydrophobic interactions in the binding site. (2) Introduction of bulky and electropositive substituents at R₃, hydrophobic substituents around rings A and E can improve the inhibition potency. (3) Nitro group at R₂ position of 2-oxindole core plays a crucial role for the biological activities, and may also be essential to the water-mediated H-bond networks. (4) For 8, 10-positions of the thiazolidinone ring and 13-position of isoxazole, the groups acting as H-bond acceptor are favorable for increasing the activity. All these results are expected to be useful in the discovery of novel and more potent MptpB inhibitors.