Abstract: Tuberculosis (TB) remains a disease with an enormous impact on public health worldwide. With the continuously increasing epidemic of drug-resistant tuberculosis, new drugs are des­perately needed. An important target enzymes of M. tuberculosis, enoyl-acyl carrier protein reductase, InhA, has been served as highly attractive targets for TB drug development. QSAR study and MD simulations have been applied to elucidate the mode of action, structural and dynamic behaviors and energetic binding affinities of InhA inhibitors towards the target sites. Ligand-based drug design approaches using 2D and 3D QSAR have been performed to identify key structural features for enhancing the potency of these inhibitors. Based on the understanding of the structure and function of the target as well as the mechanism of action of the antitubercular agents derived from the integration of advance computer-aided molecular design approaches, this study can be of primary importance into elucidate the mechanism of action of InhA inhibitors toward the target sites which are very important in identifying the effective mycobactericidal entities and, in further step, in the design and discovery of promisingly higher potential compounds against drug-resistant tuberculosis.