In Silico and In vitro Analysis of Phenolic Acids for Identification of Potential DHFR Inhibitors as Antimicrobial and Anticancer Agents.

IF 1.9 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current protein & peptide science Pub Date : 2024-01-01 DOI:10.2174/1389203724666230825142558

Renu Sehrawat, Priyanka Rathee, Pooja Rathee, Sarita Khatkar, Esra Küpeli Akkol, Anurag Khatkar

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引用次数: 0

Abstract

Background: DHFR is an indispensable enzyme required for the survival of almost all prokaryotic and eukaryotic cells, making it an attractive molecular target for drug design.

Objective: In this study, a combined in silico and in vitro approach was utilized to screen out potential anticancer and antimicrobial agents by using DHFR PDB ID 2W9S (for antimicrobial) and 1U72 (for anticancer).

Methods: Computational work was performed using Maestro Schrodinger Glide software. The DHFR inhibitory activity of the selected compounds was assessed using the DHFR test kit (CS0340-Sigma- Aldrich).

Results: Exhaustive analysis of in silico results revealed that some natural phenolic acids have a good docking score when compared to standards, i.e., trimethoprim and methotrexate, and have astonishing interactions with crucial amino acid residues available in the binding pocket of DHFR, such as Phe 92, Asp 27, Ser 49, Asn 18, and Tyr 98. In particular, digallic acid and chlorogenic acid have amazing interactions with docking scores of -9.9 kcal/mol and -9.6 kcal/mol, respectively, for the targeted protein 2W9S. Docking scores of -10.3 kcal/mol and -10.2 kcal/mol, respectively, for targeted protein 1U72. The best hits were then tested in vitro to evaluate the DHFR inhibitory activity of the compounds. DHFR inhibition activity results are in correlation with molecular docking results.

Conclusion: In silico and in vitro results confirmed the good binding and inhibitory activity of some phenolic acids to the modeled target proteins. Among all the studied natural phenolic acids, chlorogenic acid, digallic acid, and rosmarinic acid appeared to be the most potential leads for future chemical alteration. This study can provide significant speculative guidance for the design and development of potent DHFR inhibitors in the future by using these compounds as leads.

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对酚酸进行硅学和体外分析，以鉴定作为抗菌剂和抗癌剂的潜在 DHFR 抑制剂。

背景：DHFR 是几乎所有原核细胞和真核细胞生存所必需的一种不可或缺的酶，使其成为药物设计的一个有吸引力的分子靶标：在本研究中，利用 DHFR PDB IDs 2W9S （抗菌）和 1U72 （抗癌），采用硅学和体外相结合的方法筛选出潜在的抗癌和抗菌药物：计算工作使用 Maestro Schrodinger Glide 软件进行。方法：使用 Maestro Schrodinger Glide 软件进行计算，使用 DHFR 检测试剂盒（CS0340-Sigma-Aldrich）评估所选化合物的 DHFR 抑制活性：详尽的内模拟结果分析表明，与三甲双胍和甲氨蝶呤等标准化合物相比，一些天然酚酸类化合物具有良好的对接得分，并与 DHFR 结合袋中的关键氨基酸残基（如 Phe 92、Asp 27、Ser 49、Asn 18 和 Tyr 98）具有惊人的相互作用。特别是，地高辛和绿原酸与目标蛋白 2W9S 的对接得分分别为-9.9 kcal/mol 和-9.6 kcal/mol，具有惊人的相互作用。目标蛋白 1U72 的对接得分分别为 -10.3 kcal/mol 和 -10.2 kcal/mol。然后对最佳命中化合物进行体外测试，以评估其 DHFR 抑制活性。DHFR 抑制活性结果与分子对接结果一致：硅学和体外实验结果证实，一些酚酸类化合物与模型中的靶蛋白具有良好的结合力和抑制活性。在所有研究的天然酚酸中，绿原酸、地高辛酸和迷迭香酸似乎是未来最有潜力进行化学改变的线索。这项研究可以为今后以这些化合物为先导设计和开发强效 DHFR 抑制剂提供重要的推测指导。

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

Current protein & peptide science 生物-生化与分子生物学

CiteScore

5.20

自引率

0.00%

发文量

审稿时长

6 months

期刊介绍： Current Protein & Peptide Science publishes full-length/mini review articles on specific aspects involving proteins, peptides, and interactions between the enzymes, the binding interactions of hormones and their receptors; the properties of transcription factors and other molecules that regulate gene expression; the reactions leading to the immune response; the process of signal transduction; the structure and function of proteins involved in the cytoskeleton and molecular motors; the properties of membrane channels and transporters; and the generation and storage of metabolic energy. In addition, reviews of experimental studies of protein folding and design are given special emphasis. Manuscripts submitted to Current Protein and Peptide Science should cover a field by discussing research from the leading laboratories in a field and should pose questions for future studies. Original papers, research articles and letter articles/short communications are not considered for publication in Current Protein & Peptide Science.