Mohammad Z. Ahmed , Ali S. Alqahtani , Prakash kumar Shukla , Sanjit Kumar , Sudhir Kumar Pal
{"title":"基于药理的方法鉴定伤寒沙门氏菌 LpxC 酶的强效抑制剂","authors":"Mohammad Z. Ahmed , Ali S. Alqahtani , Prakash kumar Shukla , Sanjit Kumar , Sudhir Kumar Pal","doi":"10.1016/j.chphi.2024.100729","DOIUrl":null,"url":null,"abstract":"<div><p>Antimicrobial resistance (AMR) is currently a global health concern, mostly caused by microorganisms like bacteria, viruses, parasites, and fungi that acquire resistance to antimicrobial drugs. <em>Salmonella</em> is responsible for a variety of diseases but mainly cause typhoid. The primary concern is the rise in resistance in both non-typhoid and typhoid strains of this species. To address this issue, it is necessary to identify novel targets and strategies for the development of new antibacterial drugs. Lipid A, a strong bacterial endotoxin that modulates the immune system in human, is a key component of the virulence factor generated during the <em>salmonella</em> infection. Lipid A is synthesized in case of Gram-negative bacteria by cascade of nine enzyme pathway. The second step in case of Lipid A biosynthesis, catalysed by LpxC, a Zn<sup>+</sup> dependent metallo-amidase considered as rate limiting step. In this manuscript we have used protein-ligand interaction fingerprint (PLIF)–derived pharmacophore models to screen small molecules (natural products library from Zinc database, Asinex database, Thiophene analogues) against <em>Salmonella typhi</em> LpxC (<em>St</em>LpxC). Further top hit molecules were subjected to MD-simulation and ADMET studies. We identified three optimal compounds, s1_dl_mseq2, s1_ll_mseq2, and s2_ll_mseq8, that exhibit strong binding affinity towards the LpxC active site.</p></div>","PeriodicalId":9758,"journal":{"name":"Chemical Physics Impact","volume":null,"pages":null},"PeriodicalIF":3.8000,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2667022424002731/pdfft?md5=38d610f384d08307ef54819ef2fc5d74&pid=1-s2.0-S2667022424002731-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Pharmacophore-based approach for the identification of potent inhibitors against LpxC Enzyme from Salmonella Typhi\",\"authors\":\"Mohammad Z. Ahmed , Ali S. Alqahtani , Prakash kumar Shukla , Sanjit Kumar , Sudhir Kumar Pal\",\"doi\":\"10.1016/j.chphi.2024.100729\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Antimicrobial resistance (AMR) is currently a global health concern, mostly caused by microorganisms like bacteria, viruses, parasites, and fungi that acquire resistance to antimicrobial drugs. <em>Salmonella</em> is responsible for a variety of diseases but mainly cause typhoid. The primary concern is the rise in resistance in both non-typhoid and typhoid strains of this species. To address this issue, it is necessary to identify novel targets and strategies for the development of new antibacterial drugs. Lipid A, a strong bacterial endotoxin that modulates the immune system in human, is a key component of the virulence factor generated during the <em>salmonella</em> infection. Lipid A is synthesized in case of Gram-negative bacteria by cascade of nine enzyme pathway. The second step in case of Lipid A biosynthesis, catalysed by LpxC, a Zn<sup>+</sup> dependent metallo-amidase considered as rate limiting step. In this manuscript we have used protein-ligand interaction fingerprint (PLIF)–derived pharmacophore models to screen small molecules (natural products library from Zinc database, Asinex database, Thiophene analogues) against <em>Salmonella typhi</em> LpxC (<em>St</em>LpxC). Further top hit molecules were subjected to MD-simulation and ADMET studies. We identified three optimal compounds, s1_dl_mseq2, s1_ll_mseq2, and s2_ll_mseq8, that exhibit strong binding affinity towards the LpxC active site.</p></div>\",\"PeriodicalId\":9758,\"journal\":{\"name\":\"Chemical Physics Impact\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2024-09-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2667022424002731/pdfft?md5=38d610f384d08307ef54819ef2fc5d74&pid=1-s2.0-S2667022424002731-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemical Physics Impact\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2667022424002731\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Physics Impact","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2667022424002731","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
Pharmacophore-based approach for the identification of potent inhibitors against LpxC Enzyme from Salmonella Typhi
Antimicrobial resistance (AMR) is currently a global health concern, mostly caused by microorganisms like bacteria, viruses, parasites, and fungi that acquire resistance to antimicrobial drugs. Salmonella is responsible for a variety of diseases but mainly cause typhoid. The primary concern is the rise in resistance in both non-typhoid and typhoid strains of this species. To address this issue, it is necessary to identify novel targets and strategies for the development of new antibacterial drugs. Lipid A, a strong bacterial endotoxin that modulates the immune system in human, is a key component of the virulence factor generated during the salmonella infection. Lipid A is synthesized in case of Gram-negative bacteria by cascade of nine enzyme pathway. The second step in case of Lipid A biosynthesis, catalysed by LpxC, a Zn+ dependent metallo-amidase considered as rate limiting step. In this manuscript we have used protein-ligand interaction fingerprint (PLIF)–derived pharmacophore models to screen small molecules (natural products library from Zinc database, Asinex database, Thiophene analogues) against Salmonella typhi LpxC (StLpxC). Further top hit molecules were subjected to MD-simulation and ADMET studies. We identified three optimal compounds, s1_dl_mseq2, s1_ll_mseq2, and s2_ll_mseq8, that exhibit strong binding affinity towards the LpxC active site.