相关实验视频

Updated: Jul 6, 2025

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors

Published on: May 9, 2025

使用基于结构的药物发现方法发现人类二基酸脱酶的纳米分子抑制剂

William T Higgins¹, Sandip Vibhute², Chad Bennett^2,3

¹Department of Chemistry and Biochemistry, Ohio State University, Columbus, Ohio 43210, United States.

Journal of chemical information and modeling

|January 4, 2024

概括

研究人员确定了人类二基酸脱酶 (DHODH) 的新型抑制剂,这是癌症和自身免疫性疾病的标. 对于急性髓性白血病的治疗,需要新的DHODH抑制剂,为当前疗法提供替代方案.

科学领域:

药用化学医学化学
药物发现药物发现药物发现
生物化学生物化学

背景情况:

人类二甲酸脱酶 (DHODH) 是癌症,自身免疫性疾病和炎症状况的治疗点.
现有的DHODH抑制剂在治疗急性髓性白血病方面未取得成功,这凸显了对新型治疗剂的需求.
基于结构的药物发现为识别新的DHODH抑制剂提供了一个有希望的策略.

研究的目的:

通过基于结构的药物发现方法识别人类DHODH的新型小分子抑制剂.
通过实施预过步骤来发现具有有利口服可药性潜力的化合物.
寻找急性髓性白血病和其他DHODH抑制向的疾病的替代治疗剂.

主要方法:

基于结构的药物发现使用Glide SP对接分数.
预先过化合物以排除 PAINS 和 Lipinski 违规者,为口服可用药物候选物进行丰富.
生物化学试验以确定DHODH抑制的IC50值,以及基于细胞的试验以评估MOLM-13细胞活力.

主要成果:

从ChemBridge的EXPRESS-pick库中确定了20种结构独特的DHODH抑制剂,其IC50值从91nM到2.7μM不等.
十种化合物在降低MOLM-13细胞活力方面表现出有效性,IC50值在2.3微米至50.6微米之间.
化合物16显示出优异的DHODH抑制 (IC50 = 91nM) 与特里弗卢诺米德 (IC50 = 130nM) 相比,化合物17有效降低了MOLM-13细胞存活率 (IC50 = 2.3μM).

结论:

这些已识别的化合物代表了开发新型DHODH抑制剂的有希望的起点.
化合物16提供了一个强大的支架,用于进一步优化DHODH抑制剂的开发.
化合物17在急性髓性白血病细胞中表现出显著的抗增殖作用,需要进一步调查.

更多相关视频

A Semi-High-Throughput Adaptation of the NADH-Coupled ATPase Assay for Screening Small Molecule Inhibitors

A Semi-High-Throughput Adaptation of the NADH-Coupled ATPase Assay for Screening Small Molecule Inhibitors

Published on: August 17, 2019

NMR-Based Activity Assays for Determining Compound Inhibition, IC50 Values, Artifactual Activity, and Whole-Cell Activity of Nucleoside Ribohydrolases

NMR-Based Activity Assays for Determining Compound Inhibition, IC50 Values, Artifactual Activity, and Whole-Cell Activity of Nucleoside Ribohydrolases

Published on: June 30, 2019

相关概念视频

Drug Discovery: Overview

Drug Discovery: Overview

Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...

Structure-Activity Relationships and Drug Design

Structure-Activity Relationships and Drug Design

Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...