Molecular modeling and computer aided molecular design for optimal drug design of new highly potential anti-tuberculosis agents and anti-cancer agents

Molecular modeling and computer-aided molecular design approaches is becoming an essential tool in assisting fast and cost-efficient lead discovery and optimization. In the present study, molecular modeling and computer-aided molecular design approaches were applied to understand the molecular basis for developing new and more potent anti-tuberculosis (TB) and anti-cancer agents. The first target for anti-TB agents, anoyl-ACP reductase (InhA) of M. tuberculosis, has been shown to be the primary target of the isoniazid, frontline drugs. The high levels of INH resistance arise from the mutations in InhA and catalase-peroxidase (KatG) enzymes. Because of the INH resistance associated with KatG mutations, diphenyl ether and benzofuran pyrrolidine pyrazole derivatives have been developed as the direct InhA inhibitors. To achieve the structural basis to improve InhA and antimycobacterial activity, QSAR and molecular dynamics (MD) simulations were applied to elucidate beneficial information. Inhibition of bacterial and host cell signaling is a novel drug discovery concept in the second selected target of anti-TB agents. Serine/threonine protein kinase G (PknG), an enzyme in signal transduction pathways, has been identified as a promising target. MD simulations combined with 3D-QSAR studies were used to investigate the structural requirements of benzothiophene derivatives to rational design new potent PknG inhibitors. The integrated results from MD simulations and QSAR approaches provided useful structural information at the molecular level, a powerful guideline for designing effective PknG inhibitors as anti-TB agents. Moreover, a structure-based virtual screening approach was applied to identify novel scaffolds of InhA and PknG inhibitors as anti-TB agents. In an attempt to develop highly effective anti-cancer agents showing lower toxicity levels, azanaphthoquinone annelated pyrrole analogues have been developed. MD simulations and QSAR studies were applied on azanaphthoquinone derivatives to evaluate their structural features, binding mode, and binding interactions in the DNA duplex. Accordingly, the results were informative, providing key features and beneficial guidelines for further modification leading to the design of new and more potent azanaphthoquinone annelated pyrrole compounds. Newly designed compounds with higher predicted activities compared with the parent compounds and novel scaffolds of anti-TB agents and anti-cancer agents were proposed in this study.