Department of Biomedical Engineering, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, 305817, Ajmer, Rajasthan, India.
Department of Bio-Technology, Koneru Lakshmaiah Education Foundation, Vaddeswaram, AP, India.
Curr Drug Targets. 2023;24(5):388-405. doi: 10.2174/1389450124666230208102645.
Humanity has been battling with tuberculosis (TB) for a long period, and despite the availability of drugs well-known to act against the deadly microbe, the menace is still very far from reaching its end. Moreover, problems related to TB chemotherapy, such as lengthy treatment periods leading to poor patient compliance, increasing drug resistance, and association with another deadlier disease HIV-AIDS, make the situation alarming, thereby pressing the need for the discovery of new potent drugs urgently. Therefore, a drug target that is essential for survival and exclusive to M. tuberculosis presents a promising platform to explore novel molecules against the microorganism for better pathogen clearance with minimal toxicity. The shikimate pathway that leads to the synthesis of essential aromatic amino acids is one such attractive target. Shikimate kinase, the fifth enzyme of this pathway, converts shikimate to shikimate-3-phosphate by using ATP as a cosubstrate. Targeting shikimate kinase could be an effective strategy in light of its essentiality and absence of any homologue in mammals. This review discusses different strategies adopted for discovering novel compounds or scaffolds targeting M. tuberculosis shikimate kinase (MtSK) in vitro. The application of substrate analogues, their structure, and ligand-based approach for screening a library of anti-mycobacterial compounds, marine-derived molecules, and commercially available libraries have yielded promising MtSK inhibitors exhibiting micro-molar activities. To develop these leads into future drugs with minimum off-target effects on the host microenvironment, the molecules need to be structurally optimized for improved activities against enzymes and whole-cell organisms.
人类与结核病（TB）斗争已久，尽管有针对这种致命微生物的知名药物，但这种威胁仍远未结束。此外，与结核病化疗相关的问题，如治疗期长导致患者依从性差、药物耐药性增加以及与另一种更致命的疾病 HIV-AIDS 相关，使情况令人担忧，因此迫切需要发现新的有效药物。因此，对于 M. tuberculosis 来说必不可少且独有的药物靶点为探索针对该微生物的新型分子提供了一个有前途的平台，以实现最小毒性的更好病原体清除。导致必需芳香族氨基酸合成的莽草酸途径就是这样一个有吸引力的目标。该途径的第五种酶——莽草酸激酶，利用 ATP 作为辅助底物，将莽草酸转化为莽草酸-3-磷酸。鉴于其重要性和在哺乳动物中没有同源物，靶向莽草酸激酶可能是一种有效的策略。本综述讨论了为体外发现针对结核分枝杆菌莽草酸激酶（MtSK）的新型化合物或支架而采用的不同策略。底物类似物的应用、它们的结构以及基于配体的方法用于筛选抗分枝杆菌化合物文库、海洋衍生分子和市售文库，已经产生了具有微摩尔活性的有前途的 MtSK 抑制剂。为了将这些先导化合物开发成对宿主微环境的脱靶效应最小的未来药物，需要对这些分子进行结构优化，以提高对酶和全细胞生物的活性。
