Computational Design of Phosphatidylinositol 3-Kinase Inhibitors.

IF 1.6 4区医学 Q4 BIOCHEMICAL RESEARCH METHODS

Assay and drug development technologies Pub Date : 2022-10-01 DOI:10.1089/adt.2022.057

Isha Rani, Anju Goyal, M Sharma

引用次数: 5

Abstract

One of the most sought-after therapeutic targets for treating human cancers is the phosphoinositide 3-kinase; PI3k is an integral part of the PI3K/protein kinase B signaling arcade. This pathway is frequently activated in malignancies. Drug resistance and dose-limiting adverse effects are currently associated challenges with the existing anticancer chemotherapy. Therefore, in this research, a series of pyrimidine derivatives were designed and evaluated against human PI3K by using molecular docking analysis. The docking results were further verified by molecular dynamic simulation, which analyzed the strength of the macromolecular complex with respect to time. Compounds IV and XIV were found to be the most potent inhibitors of the human PI3K receptor with a high degree of stability within the active site of the target receptor for a timeframe of 50 ns. Thus, both of these compounds could be important drug candidates for the development of PI3K inhibitors as a prospective anticancer agent.

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磷脂酰肌醇3激酶抑制剂的计算设计。

治疗人类癌症最受欢迎的治疗靶点之一是磷酸肌肽3-激酶;PI3k是PI3k /蛋白激酶B信号通路的一个组成部分。这一途径在恶性肿瘤中经常被激活。耐药和剂量限制性不良反应是目前与现有抗癌化疗相关的挑战。因此，本研究设计了一系列嘧啶衍生物，并通过分子对接分析对其与人PI3K的关系进行了评价。通过分子动力学模拟进一步验证了对接结果，分析了大分子复合物相对于时间的强度。化合物IV和XIV被发现是人类PI3K受体最有效的抑制剂，在目标受体的活性位点内具有高度的稳定性，时间范围为50 ns。因此，这两种化合物可能是开发PI3K抑制剂的重要候选药物，作为一种有前景的抗癌药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Assay and drug development technologies 医学-生化研究方法

CiteScore

3.60

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： ASSAY and Drug Development Technologies provides access to novel techniques and robust tools that enable critical advances in early-stage screening. This research published in the Journal leads to important therapeutics and platforms for drug discovery and development. This reputable peer-reviewed journal features original papers application-oriented technology reviews, topical issues on novel and burgeoning areas of research, and reports in methodology and technology application. ASSAY and Drug Development Technologies coverage includes: -Assay design, target development, and high-throughput technologies- Hit to Lead optimization and medicinal chemistry through preclinical candidate selection- Lab automation, sample management, bioinformatics, data mining, virtual screening, and data analysis- Approaches to assays configured for gene families, inherited, and infectious diseases- Assays and strategies for adapting model organisms to drug discovery- The use of stem cells as models of disease- Translation of phenotypic outputs to target identification- Exploration and mechanistic studies of the technical basis for assay and screening artifacts