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。

IF 3.8 2区 化学 Q2 CHEMISTRY, APPLIED
Adrija Banerjee, Gatta K R S Naresh, Lalitha Guruprasad
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引用次数: 0

摘要

由病毒、细菌和真菌病原体引起的医院获得性感染(HAIs)在世界各地造成了大量死亡。肺炎克雷伯菌(Kp)是一种耐药革兰氏阴性菌,可引起HAIs。天冬氨酸β-半醛脱氢酶(ASADH)酶对Kp的存活至关重要,因为它参与了必需氨基酸和重要代谢物的产生的生物合成途径。这种途径在哺乳动物中不存在,因此设计Kp ASADH抑制剂成为治疗HAIs的良好策略。在本研究中,采用计算方法设计针对Kp ASADH的抑制剂。通过分析与两种已建立的先导化合物(4-硝基-2-膦苯甲酸和(S)-甲基半胱氨酸亚砜)的结合相互作用,确定了关键活性位点残基。利用辅酶NADPH存在的活性位点内的分子对接,从NCI多样性数据库中对化合物进行虚拟筛选。随后对鉴定出的击中化合物的类药物性质进行了评估。使用分子动力学模拟进一步验证了这些分子,以评估其结构稳定性。通过正态分析、机械刚度评估、主成分分析和结合能计算,对最终命中的化合物进行了额外的稳定性评估。对最终化合物的ADMET谱进行了检测。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
Molecular Diversity
Molecular Diversity 化学-化学综合
CiteScore
7.30
自引率
7.90%
发文量
219
审稿时长
2.7 months
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;
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