{"title":"对幽门螺杆菌 dUTP 酶进行分子分析,利用硅学研究鉴定新型抑制剂。","authors":"Rinki Sisodia, Debapriyo Sarmadhikari, Pooja Anjali Mazumdar, Shailendra Asthana, Chaithanya Madhurantakam","doi":"10.1080/07391102.2023.2247080","DOIUrl":null,"url":null,"abstract":"<p><p>The human gastric pathogen <i>Helicobacter pylori</i> 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 <i>H. pylori</i> 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 <i>Helicobacter pylori</i> dUTPase protein. We conclude that our proposed molecules may be potential lead molecules for effective inhibition against the <i>H. pylori</i> dUTPase protein subject to experimental validation.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Molecular analysis of dUTPase of <i>Helicobacter pylori</i> for identification of novel inhibitors using <i>in silico</i> studies.\",\"authors\":\"Rinki Sisodia, Debapriyo Sarmadhikari, Pooja Anjali Mazumdar, Shailendra Asthana, Chaithanya Madhurantakam\",\"doi\":\"10.1080/07391102.2023.2247080\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The human gastric pathogen <i>Helicobacter pylori</i> 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 <i>H. pylori</i> 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 <i>Helicobacter pylori</i> dUTPase protein. We conclude that our proposed molecules may be potential lead molecules for effective inhibition against the <i>H. pylori</i> dUTPase protein subject to experimental validation.Communicated by Ramaswamy H. Sarma.</p>\",\"PeriodicalId\":15272,\"journal\":{\"name\":\"Journal of Biomolecular Structure & Dynamics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Biomolecular Structure & Dynamics\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1080/07391102.2023.2247080\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/8/17 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biomolecular Structure & Dynamics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1080/07391102.2023.2247080","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/8/17 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Molecular analysis of dUTPase of Helicobacter pylori for identification of novel inhibitors using in silico studies.
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.
期刊介绍:
The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.