Adrija Banerjee, Gatta K R S Naresh, Lalitha Guruprasad
{"title":"针对医院获得性感染的肺炎克雷伯菌天冬氨酸半醛脱氢酶抑制剂设计。","authors":"Adrija Banerjee, Gatta K R S Naresh, Lalitha Guruprasad","doi":"10.1007/s11030-025-11277-5","DOIUrl":null,"url":null,"abstract":"<p><p>Hospital-acquired infections (HAIs) caused by viral, bacterial, and fungal pathogens have resulted in numerous deaths all over the world. Klebsiella pneumoniae (Kp) is a drug-resistant Gram-negative bacterium responsible for HAIs. Aspartate β-semialdehyde dehydrogenase (ASADH) enzyme is crucial for the survival of Kp since it is involved in the biosynthetic pathway responsible for the production of essential amino acids and important metabolites. This pathway is absent in mammals and hence design of inhibitors for Kp ASADH becomes a good strategy for the treatment of HAIs. In this study, computational methodologies were employed to design inhibitors targeting Kp ASADH. Key active site residues were identified through the analysis of binding interactions with two established lead compounds, 4-nitro-2-phosphonobenzoic acid and (S)-methyl cysteine sulfoxide. A virtual screening of compounds from the NCI Diversity Database was conducted using molecular docking within the active site in the presence of coenzyme NADPH. Drug-like properties of the identified hit compounds were subsequently evaluated. These molecules were further validated using molecular dynamics simulations to assess their structural stability. The finalized hit compounds underwent additional stability assessments through normal mode analysis, mechanical stiffness evaluation, principal component analysis, and binding energy calculations using MM/GBSA. ADMET profiles of the final compounds were examined.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design of inhibitors to Klebsiella pneumoniae aspartate semialdehyde dehydrogenase towards hospital-acquired infections.\",\"authors\":\"Adrija Banerjee, Gatta K R S Naresh, Lalitha Guruprasad\",\"doi\":\"10.1007/s11030-025-11277-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Hospital-acquired infections (HAIs) caused by viral, bacterial, and fungal pathogens have resulted in numerous deaths all over the world. Klebsiella pneumoniae (Kp) is a drug-resistant Gram-negative bacterium responsible for HAIs. Aspartate β-semialdehyde dehydrogenase (ASADH) enzyme is crucial for the survival of Kp since it is involved in the biosynthetic pathway responsible for the production of essential amino acids and important metabolites. This pathway is absent in mammals and hence design of inhibitors for Kp ASADH becomes a good strategy for the treatment of HAIs. In this study, computational methodologies were employed to design inhibitors targeting Kp ASADH. Key active site residues were identified through the analysis of binding interactions with two established lead compounds, 4-nitro-2-phosphonobenzoic acid and (S)-methyl cysteine sulfoxide. A virtual screening of compounds from the NCI Diversity Database was conducted using molecular docking within the active site in the presence of coenzyme NADPH. Drug-like properties of the identified hit compounds were subsequently evaluated. These molecules were further validated using molecular dynamics simulations to assess their structural stability. The finalized hit compounds underwent additional stability assessments through normal mode analysis, mechanical stiffness evaluation, principal component analysis, and binding energy calculations using MM/GBSA. ADMET profiles of the final compounds were examined.</p>\",\"PeriodicalId\":708,\"journal\":{\"name\":\"Molecular Diversity\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2025-07-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Diversity\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1007/s11030-025-11277-5\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, APPLIED\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Diversity","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1007/s11030-025-11277-5","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Design of inhibitors to Klebsiella pneumoniae aspartate semialdehyde dehydrogenase towards hospital-acquired infections.
Hospital-acquired infections (HAIs) caused by viral, bacterial, and fungal pathogens have resulted in numerous deaths all over the world. Klebsiella pneumoniae (Kp) is a drug-resistant Gram-negative bacterium responsible for HAIs. Aspartate β-semialdehyde dehydrogenase (ASADH) enzyme is crucial for the survival of Kp since it is involved in the biosynthetic pathway responsible for the production of essential amino acids and important metabolites. This pathway is absent in mammals and hence design of inhibitors for Kp ASADH becomes a good strategy for the treatment of HAIs. In this study, computational methodologies were employed to design inhibitors targeting Kp ASADH. Key active site residues were identified through the analysis of binding interactions with two established lead compounds, 4-nitro-2-phosphonobenzoic acid and (S)-methyl cysteine sulfoxide. A virtual screening of compounds from the NCI Diversity Database was conducted using molecular docking within the active site in the presence of coenzyme NADPH. Drug-like properties of the identified hit compounds were subsequently evaluated. These molecules were further validated using molecular dynamics simulations to assess their structural stability. The finalized hit compounds underwent additional stability assessments through normal mode analysis, mechanical stiffness evaluation, principal component analysis, and binding energy calculations using MM/GBSA. ADMET profiles of the final compounds were examined.
期刊介绍:
Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including:
combinatorial chemistry and parallel synthesis;
small molecule libraries;
microwave synthesis;
flow synthesis;
fluorous synthesis;
diversity oriented synthesis (DOS);
nanoreactors;
click chemistry;
multiplex technologies;
fragment- and ligand-based design;
structure/function/SAR;
computational chemistry and molecular design;
chemoinformatics;
screening techniques and screening interfaces;
analytical and purification methods;
robotics, automation and miniaturization;
targeted libraries;
display libraries;
peptides and peptoids;
proteins;
oligonucleotides;
carbohydrates;
natural diversity;
new methods of library formulation and deconvolution;
directed evolution, origin of life and recombination;
search techniques, landscapes, random chemistry and more;