Bora Nikita, Jha Anupam Nath
Computational Biophysics Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, India.
Front Genet. 2020 Mar 6;11:179. doi: 10.3389/fgene.2020.00179. eCollection 2020.
The protozoan , from trypanosomatids family is a deadly human pathogen responsible for causing Visceral Leishmaniasis. Unavailability of proper treatment in the developing countries has served as a major threat to the people. The absence of vaccines has made treatment possibilities to rely solely over chemotherapy. Also, reduced drug efficacy due to emerging resistant strains magnifies the threat. Despite years of formulations for an effective drug therapy, complexity of the disease is also unfortunately increasing. Absence of potential drug targets has worsened the scenario. Therefore exploring new therapeutic approach is a priority for the scientific community to combat the disease. One of the most reliable ways to alter the adversities of the infection is finding new biological targets for designing potential drugs. An era of computational biology allows identifying targets, assisting experimental studies. It includes sorting the parasite's metabolic pathways that pins out proteins essential for its survival. We have directed our study towards a computational methodology for determining targets against from the "purine salvage" pathway. This is a mainstay pathway towards the maintenance of purine amounts in the parasitic pool of nutrients proving to be mandatory for its survival. This study represents an integration of metabolic pathway and Protein-Protein Interactions analysis. It consists of incorporating the available experimental data to the theoretical methods with a prospective to develop a kinetic model of Purine salvage pathway. Simulation data revealed the time course mechanism of the enzymes involved in the synthesis of the metabolites. Modeling of the metabolic pathway helped in marking of crucial enzymes. Additionally, the PPI analysis of the pathway assisted in building a static interaction network for the proteins. Topological analysis of the PPI network through centrality measures (MCC and Closeness) detected targets found common with Dynamic Modeling. Therefore our analysis reveals the enzymes ADSL (Adenylosuccinate lyase) and IMPDH (Inosine-5'-monophosphate dehydrogenase) to be important having a central role in the modeled network based on PPI and kinetic modeling techniques. Further the available three dimensional structure of the enzyme "ADSL" aided towards the search for potential inhibitors against the protein. Hence, the study presented the significance of integrating methods to identify key proteins which might be putative targets against the treatment of Visceral Leishmaniasis and their potential inhibitors.
来自锥虫科的原生动物是一种致命的人类病原体，可导致内脏利什曼病。发展中国家缺乏适当的治疗方法，这对人们构成了重大威胁。由于没有疫苗，治疗只能完全依赖化疗。此外，新出现的耐药菌株导致药物疗效降低，这进一步加剧了威胁。尽管多年来一直在研发有效的药物疗法，但不幸的是，这种疾病的复杂性也在增加。缺乏潜在的药物靶点使情况更加恶化。因此，探索新的治疗方法是科学界对抗这种疾病的当务之急。改变感染不利状况的最可靠方法之一是找到新的生物学靶点来设计潜在药物。计算生物学时代使得识别靶点成为可能，并有助于实验研究。这包括梳理寄生虫的代谢途径，找出其生存所必需的蛋白质。我们将研究方向指向一种计算方法，用于确定针对“嘌呤补救”途径的靶点。这是维持寄生虫营养池中嘌呤含量的主要途径，对其生存至关重要。这项研究将代谢途径分析和蛋白质-蛋白质相互作用分析结合在一起。它包括将现有的实验数据与理论方法相结合，以期建立嘌呤补救途径的动力学模型。模拟数据揭示了参与代谢物合成的酶的时间进程机制。代谢途径的建模有助于标记关键酶。此外，该途径的蛋白质-蛋白质相互作用分析有助于构建蛋白质的静态相互作用网络。通过中心性度量（MCC和接近度）对蛋白质-蛋白质相互作用网络进行拓扑分析，检测到与动态建模共同的靶点。因此，我们的分析表明，腺苷琥珀酸裂解酶（ADSL）和肌苷-5'-单磷酸脱氢酶（IMPDH）这两种酶很重要，在基于蛋白质-蛋白质相互作用和动力学建模技术的模型网络中起着核心作用。此外，酶“ADSL”的现有三维结构有助于寻找针对该蛋白质的潜在抑制剂。因此，这项研究展示了整合多种方法来识别关键蛋白质的重要性，这些关键蛋白质可能是治疗内脏利什曼病的假定靶点及其潜在抑制剂。
