Inhibition of Cyclooxygenase-2 and Thymidylate Synthase by Dietary Sphingomyelins: Insights from DFT and Molecular Docking Studies

IF 1.4 Q3 CHEMISTRY, MULTIDISCIPLINARY

Physical Chemistry Research Pub Date : 2020-06-01 DOI:10.22036/PCR.2020.214026.1717

M. Abdul-Hammed, B. Semire, Ebhohimen Ehizuelen Israel, A. Oyebamiji, T. Olowolafe

{"title":"Inhibition of Cyclooxygenase-2 and Thymidylate Synthase by Dietary Sphingomyelins: Insights from DFT and Molecular Docking Studies","authors":"M. Abdul-Hammed, B. Semire, Ebhohimen Ehizuelen Israel, A. Oyebamiji, T. Olowolafe","doi":"10.22036/PCR.2020.214026.1717","DOIUrl":null,"url":null,"abstract":"Inhibition of cyclooxygenase-2 (COX-2) and thymidylate Synthase (TS) enzymes play prominent chemopreventive and chemotherapeutic roles in colorectal cancer studies. Basic computational investigation on the inhibition of these enzymes by sphingomyelin (SM) derivatives was carried out in silico using Density Functional Theory (DFT) and molecular docking studies. Interactions between SM with unsaturated fatty acids, COX-2 and TS were compared with that of 5-Fluorouracil (5-FU) and Celecoxib, the standard anti-colorectal cancer drugs. The results showed that SM with alpha-linoleic acid derivative possesses the highest HOMO (-4.70 eV) and lowest LUMO (0.09 eV) energies, which may enhance their interactions with their target receptors. All SM molecules, irrespective of the fatty acid nature have lower binding affinities, (ΔG = -5.5 to - 6.8 kcal/mol) against COX-2 than Celecoxib (-10.1 kcal/mol), indicating that the standard COX-2 inhibitor is much stronger than the natural SM. However, some of the natural SM are stronger inhibitors of thymidylate synthase than the standard drug, 5-FU, with SM having alpha-linoleic acid derivative (ΔG = - 6.2 kcal/mol) higher than 5-FU (ΔG = -5.28 kcal/mol), but lower than that of the active drug metabolite, 5-FdUMP (ΔG = - 7.4 kcal/mol). These ligand-protein interactions were all feasible and spontaneous.","PeriodicalId":20084,"journal":{"name":"Physical Chemistry Research","volume":null,"pages":null},"PeriodicalIF":1.4000,"publicationDate":"2020-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Physical Chemistry Research","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.22036/PCR.2020.214026.1717","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}

引用次数: 1

Abstract

Inhibition of cyclooxygenase-2 (COX-2) and thymidylate Synthase (TS) enzymes play prominent chemopreventive and chemotherapeutic roles in colorectal cancer studies. Basic computational investigation on the inhibition of these enzymes by sphingomyelin (SM) derivatives was carried out in silico using Density Functional Theory (DFT) and molecular docking studies. Interactions between SM with unsaturated fatty acids, COX-2 and TS were compared with that of 5-Fluorouracil (5-FU) and Celecoxib, the standard anti-colorectal cancer drugs. The results showed that SM with alpha-linoleic acid derivative possesses the highest HOMO (-4.70 eV) and lowest LUMO (0.09 eV) energies, which may enhance their interactions with their target receptors. All SM molecules, irrespective of the fatty acid nature have lower binding affinities, (ΔG = -5.5 to - 6.8 kcal/mol) against COX-2 than Celecoxib (-10.1 kcal/mol), indicating that the standard COX-2 inhibitor is much stronger than the natural SM. However, some of the natural SM are stronger inhibitors of thymidylate synthase than the standard drug, 5-FU, with SM having alpha-linoleic acid derivative (ΔG = - 6.2 kcal/mol) higher than 5-FU (ΔG = -5.28 kcal/mol), but lower than that of the active drug metabolite, 5-FdUMP (ΔG = - 7.4 kcal/mol). These ligand-protein interactions were all feasible and spontaneous.

查看原文本刊更多论文

膳食鞘氨醇对环氧合酶-2和胸苷酸合成酶的抑制作用：DFT和分子对接研究的启示

环氧化酶-2（COX-2）和胸苷酸合成酶（TS）的抑制在结直肠癌癌症研究中发挥着显著的化学预防和化学治疗作用。利用密度泛函理论（DFT）和分子对接研究，在计算机上对鞘磷脂（SM）衍生物对这些酶的抑制作用进行了基础计算研究。将SM与不饱和脂肪酸、COX-2和TS的相互作用与抗癌症标准药物5-氟尿嘧啶（5-FU）和塞来昔布的相互作用进行比较。结果表明，具有α-亚油酸衍生物的SM具有最高的HOMO（-4.70eV）和最低的LUMO（0.09eV）能量，这可能增强它们与靶受体的相互作用。所有SM分子，无论脂肪酸性质如何，对COX-2的结合亲和力（ΔG=-5.5至-6.8 kcal/mol）均低于塞来昔布（-10.1 kcal/mol，SM的α-亚油酸衍生物（ΔG=-6.2 kcal/mol）高于5-FU（ΔG=5.28 kcal/mol。这些配体-蛋白质相互作用都是可行的并且是自发的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Physical Chemistry Research CHEMISTRY, MULTIDISCIPLINARY-

CiteScore

2.70

自引率

8.30%

发文量

期刊介绍： The motivation for this new journal is the tremendous increasing of useful articles in the field of Physical Chemistry and the related subjects in recent years, and the need of communication between Physical Chemists, Physicists and Biophysicists. We attempt to establish this fruitful communication and quick publication. High quality original papers in English dealing with experimental, theoretical and applied research related to physics and chemistry are welcomed. This journal accepts your report for publication as a regular article, review, and Letter. Review articles discussing specific areas of physical chemistry of current chemical or physical importance are also published. Subjects of Interest: Thermodynamics, Statistical Mechanics, Statistical Thermodynamics, Molecular Spectroscopy, Quantum Chemistry, Computational Chemistry, Physical Chemistry of Life Sciences, Surface Chemistry, Catalysis, Physical Chemistry of Electrochemistry, Kinetics, Nanochemistry and Nanophysics, Liquid Crystals, Ionic Liquid, Photochemistry, Experimental article of Physical chemistry. Mathematical Chemistry.