Modeling of new potential inhibitors of dihydrofolate reductase based on 1,3,4-thiadiazole amidoalkyl derivatives

Q4 Chemistry

Voprosy Khimii i Khimicheskoi Tekhnologii Pub Date : 2023-10-01 DOI:10.32434/0321-4095-2023-150-5-91-97

V.V. Pavlova, P.V. Zadorozhnii, V.V. Kiselev, A.V. Kharchenko, O.V. Okhtina

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引用次数: 0

Abstract

Derivatives of 1,3,4-thiadiazole are very important for medical chemistry and pharmacy as potential drug substances. In this work, we carried out molecular docking studies of amidoalkyl derivatives of 1,3,4-thiadiazole: N-(2,2,2-trichloro-1-((5-aryl-1,3,4-thiadiazol-2-yl)amino)ethyl)carboxamides and N-(2,2,2-trichloro-1-((5-(arylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)carboxamides with dihydrofolate reductase (DHFR). The AutoDock Vina program based on the PyRx 0.8 platform was used for docking. Before docking, the enzyme structure (PDB ID: 1DLS) was prepared using the Chimera 1.14 program, and the structures of potential inhibitors and reference preparations were optimized by the PM3 method in the ArgusLab 4.0.1 program. According to the results of molecular docking, the analyzed compounds effectively interact with the active site of DHFR. It is shown that the introduction of an NH group between the 1,3,4-thiadiazole and aromatic rings leads to stronger binding of ligands to DHFR. Based on the results of molecular docking, the following hit compounds were selected: 4-methyl-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide and 4-methyl-N-(2,2,2-trichloro-1-((5-(p-tolylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide, which are superior to the reference compounds according to the strength of the formed complex.

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基于1,3,4-噻二唑酰胺烷基衍生物的新型潜在二氢叶酸还原酶抑制剂的建模

1,3,4-噻二唑衍生物作为潜在的原料药，在医学化学和药学领域具有重要意义。在这项工作中，我们对1,3,4-噻二唑的酰胺烷基衍生物:N-(2,2,2-三氯-1-((5-芳基1,3,4-噻二唑-2-基)氨基)乙基)羧酰胺和N-(2,2,2-三氯-1-((5-(芳基)-1,3,4-噻二唑-2-基)氨基)乙基)羧酰胺与二氢叶酸还原酶(DHFR)进行了分子对接研究。对接使用基于PyRx 0.8平台的AutoDock Vina程序。对接前，使用Chimera 1.14程序制备酶结构(PDB ID: 1DLS)，并在ArgusLab 4.0.1程序中使用PM3方法优化潜在抑制剂和参比制剂的结构。根据分子对接结果，分析的化合物与DHFR活性位点有效相互作用。结果表明，在1,3,4-噻二唑环和芳香环之间引入一个NH基团导致配体与DHFR的结合更强。根据分子对接的结果，选择了以下hit化合物:4-甲基- n -(2,2,2-三氯-1-((5-(苯基氨基)-1,3,4-噻二唑-2-基)氨基)乙基)苯酰胺和4-甲基- n -(2,2,2-三氯-1-((5-(对苯基氨基)-1,3,4-噻二唑-2-基)氨基)乙基)苯酰胺，根据形成的配合物的强度优于对照化合物。

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来源期刊

Voprosy Khimii i Khimicheskoi Tekhnologii Chemical Engineering-Chemical Engineering (all)

CiteScore

0.90

自引率

0.00%

发文量

期刊介绍： Voprosy Khimii i Khimicheskoi Tekhnologii (Issues of Chemistry and Chemical Technology) is published bimonthly by the Ukrainian State University of Chemical Technology and accepts Ukrainian- or English language high-quality original articles and reviews concerning various fields of research in chemistry and chemical engineering. Our unusual title “Voprosy khimii i khimicheskoi tekhnologii” originates from the transliterated initial Russian title “Issues of Chemistry and Chemical Technology“. The fact of the matter is that Voprosy khimii i khimicheskoi tekhnologii was founded in 1965 as a scientific journal mainly for Russian-reading and Russian-speaking readership when «the Iron Curtain» existed. Since 1991, after Ukraine declared its independence, our Journal began to publish the articles in Ukrainian and English. Multilingualism is our established tradition. We remember and cherish our traditions, but we follow the latest trends in modern science. Papers that are multidisciplinary or address new or emerging areas of chemistry and chemical engineering are particularly encouraged. Thus, the scope is dynamic. It includes but is not limited to the traditional areas of general, inorganic, organic, analytical, physical chemistry and electrochemistry, as well as all conventional areas of chemical engineering (chemistry of high molecular compounds, technology of inorganic and organic substances, processing of combustible minerals, chemical technology of silicates, processes and apparatus of chemical productions, etc.). The Journal publishes papers dealing with newer interdisciplinary areas such as materials science, nano-science, catalysis, computational and theoretical chemistry, surface phenomenon and colloidal systems, environmental chemistry, green chemistry.