Molecular modelling investigation on 4-aminoquinoline derivatives as potent anti-tubercular agents

Abstract

The emergency of new Mycobacterium tuberculosis strains leads to multi-drug resistant tuberculosis (MDR) and total drug resistant tuberculosis (TDR) indicating the urgency in the development of newer anti-tubercular agents to be effective against the resistance strains. In the present study pharmacophore modelling and atom-based 3D-QSAR of 4-Aminoquinoline derivatives was carried out to understand the key structural features responsible for anti-tb activity. Phase module of Schrödinger was used to generate a five-point Pharmacophore for 46 molecules belonging to 4-Aminoquinolines. The best scoring hypothesis (ADHHR_1) had one H-bond Acceptor (A1), one H-bond donor (D5), two Hydrophobic regions (H10 and H11) and one Ring (R14) with a good regression coefficient of 0.9604. The validity of the hypothesis was judged by the cross-validation coefficient (Q2= 0.7885) and Pearson- r (0.9158) followed by the external validation which showed high predictive power. Newer molecules were designed and subjected to molecular docking to explore the alleged binding modes followed by molecular dynamic simulation studies. The molecular modelling study revealed the significance of aromatic ring and hydrogen bond responsible for potent anti-tb activity.