Molecular analysis of dUTPase of Helicobacter pylori for identification of novel inhibitors using in silico studies

生物信息学 计算生物学 小分子 虚拟筛选 幽门螺杆菌 药物发现 人口 化学 对接(动物) 结合位点 蛋白质-蛋白质相互作用 生物 生物化学 遗传学 基因 社会学 人口学 护理部 医学
作者
Rinki Sisodia,Debapriyo Sarmadhikari,P.A. Mazumdar,Shailendra Asthana,Chaithanya Madhurantakam
出处
期刊:Journal of Biomolecular Structure & Dynamics [Taylor & Francis]
卷期号:: 1-26 被引量:1
标识
DOI:10.1080/07391102.2023.2247080
摘要

The human gastric pathogen Helicobacter pylori chronically affects the gastric mucosal layer of approximately half of world's population. The emergence of resistant strains urges the need for identification of novel and selective drug against new molecular targets. A ubiquitous enzyme, Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), is considered as first line of defense against uracil mis-incorporation into DNA, and essential for genome integrity. Lack of dUTPase triggers an elevated recombination frequency, DNA breaks and ultimately cell death. Hence, dUTPase can be considered as a promising target for development of novel lead inhibitor compounds in H. pylori treatment. Herein, we report the generation of three-dimensional model of the target protein using comparative modelling and its validation. To identify dUTPase inhibitors, a high throughput virtual screening approach utilizing Knowledge-based inhibitors and DrugBank database was implemented. Top ranked compounds were scrutinized based on investigations of the protein-ligand interaction fingerprints, molecular interaction maps and binding affinities and the drug potentiality. The best ligands were studied further for complex stability and intermolecular interaction profiling with respect to time under 100 ns classical molecular dynamic stimulation, establishing significant stability in dynamic states as observed from RMSD and RMSF parameters and interactions with the catalytic site residues. The binding free energy calculation computed using MM-GBSA method from the MD simulation trajectories demonstrated that our molecules possess strong binding affinity towards the Helicobacter pylori dUTPase protein. We conclude that our proposed molecules may be potential lead molecules for effective inhibition against the H. pylori dUTPase protein subject to experimental validation.Communicated by Ramaswamy H. Sarma.
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