Design, synthesis and biological evaluation of enzyme inhibitors

Abstract

Drug discovery and development are time-intensive process and demand countless resources. The issue can be addressed by implementing computational strategies that correlate the chemical properties of a molecule with its biological properties and streamline the discovery, development, and optimization of the proposed drug candidate. It is collectively referred to as computer-aided drug design (CADD), in silico or rational drug design. CADD includes mainly two approaches: i) structure-based drug design (SBDD) that involves molecular docking study, and ii) ligand-based drug design (LBDD), which comprises the study of quantitative structure-activity relationship (QSAR). Recently, the direction of drug development has been shifted towards the targeted action of bioactive compounds. Various characteristic biomarkers have been identified as targets for diagnosis and therapy of cancer. One such biomarker for prostate cancer is prostate-specific membrane antigen (PSMA), also called glutamate carboxypeptidase II (GCPII). It is expressed in the prostate gland's epithelial cells, which immensely increases in the cancerous state. The extent of upregulation is an excellent indicator of the advancement of prostate cancer. Therefore, the development of PSMA targeting ligands and their conjugation with various diagnostic tools like radionuclear isotopes, near-infrared (NIR) dyes, or magnetic nanoparticles is considered one of the core strategies for prostate cancer prognosis, diagnosis, and therapy. It is essential in cancer therapy to identify the critical biological processes that are important in cancer progression. One such process is the formation of microtubules, which is much more pronounced in cancerous conditions. Microtubules are involved in cellular morphology, control of intracellular transportation, regulation of mitotic spindle fibre formation, and cell division. Several anticancer agents have been developed, which disrupt microtubule formation by inhibition of polymerization or depolymerization of α-β tubulin heterodimer. Tubulysins are a potent class of anticancer agents that inhibit tubulin heterodimer polymerization and disrupt the cell division process. However, tubulysin’s clinical development to an approved drug for commercial use has been hampered due to structural complexities and low yield from biosynthesis. Therefore, research focus has now been shifted to developing potent and synthetically feasible tubulysin derivatives for cancer therapy. The thesis's main objective is to apply in silico strategies to design and synthesize new small molecule ligands or inhibitors and ligand conjugates with the potential for cancer diagnosis and treatment.