Kechi Eban L, Ubah Chioma B, Runde Musa, Owen Aniekan E, Godfrey Obinna C, Agurokpon Daniel C, Odey Michael O, Edet Uwem O, Ekpong Bassey O, Iyam Solomon O, Benjamin Innocent, Sampathkumar Gopinath
Department of Genetics and Biotechnology, University of Calabar, Calabar, Nigeria.
Department of Pharmacology, University of Calabar, Calabar, Nigeria.
In Silico Pharmacol. 2024 May 30;12(1):48. doi: 10.1007/s40203-024-00222-3. eCollection 2024.
The continuous search for more effective options against well-known pathogens such as remains the rationale for the search for novel lead compounds from various sources. This study aims to investigate the chemical structure, chemical properties, of 5-(2-((5-(((1S,3R) -3-(5-acetamido-1,3,4-thiadiazolidin-2-yl) cyclopentyl) methyl)-1,3,4-thiadiazolidin-2-yl)amino)-2-oxoethyl)-2-methyl-2,3-dihydro-1H-pyrazol-3-ide designated ATCTP using DFT method ωB97XD/-311 + + g(2d, 2p) and the biological potential of compound ATCTP against using molecular docking and ADMET studies. Geometry optimization was carried out in DMSO, ethanol. gas and water revealing minute discrepancies in bond length and wider differences in bond angles. Frontier molecular orbital investigations reveal HOMO-LUMO energy gap magnitude in decreasing order of ATCTP_Gas > ATCTP_Water > ATCTP_ethanol > ATCTP_DMSO inferring that water influences chemical stability of the compound the most compared to ethanol and DMSO. Density of state investigations have revealed electron density contributions at corresponding energy peaks. In silico pharmacokinetic predicts ATCTP not to be cytotoxic, hepatotoxic, immunotoxic or mutagenic but probable mutagen. Molecular docking investigation of ATCTP against aspartic proteinase of (ID: 2QZX) in comparison with standard drug Fluconazole. Compound ATCTP had higher binding affinity (- 8.1 kcal/mol) compared to that of the standard drug fluconazole (- 5.6 kcal/mol) which records 4 conventional hydrogen interactions compared to 2 formed in the interaction of ATCTP + 2QZX. ATCTP also reports binding affinity of - 7.2 kcal/mol which reportedly surpassed that of 2QZX interaction with fluconazole (- 5.7 kcal/mol). ATCTP binds with lanosterol14-α-demethylase (5v5z) with binding affinity of - 9.7 kcal/mol binding to active site amino acid residues of the protein compared to fluconazole + 5v5z (- 8.0 kcal/mol). ATCTP is therefore recommended to be a lead compound for the possible design of a new and more effective anti-candida therapeutic compound.
持续寻找针对知名病原体（如……）更有效的选择，仍然是从各种来源寻找新型先导化合物的基本原理。本研究旨在使用DFT方法ωB97XD/-311++g(2d, 2p)研究5-(2-((5-(((1S,3R)-3-(5-乙酰氨基-1,3,4-噻二唑烷-2-基)环戊基)甲基)-1,3,4-噻二唑烷-2-基)氨基)-2-氧代乙基)-2-甲基-2,3-二氢-1H-吡唑-3-化物（命名为ATCTP）的化学结构、化学性质，以及通过分子对接和ADMET研究该化合物ATCTP对……的生物活性。在二甲基亚砜、乙醇、气相和水中进行了几何优化，结果显示键长存在微小差异，键角差异较大。前沿分子轨道研究表明，ATCTP_气相>ATCTP_水>ATCTP_乙醇>ATCTP_二甲基亚砜的HOMO-LUMO能隙大小依次递减，这表明与乙醇和二甲基亚砜相比，水对该化合物化学稳定性的影响最大。态密度研究揭示了相应能量峰处的电子密度贡献。计算机模拟药代动力学预测ATCTP无细胞毒性、肝毒性、免疫毒性或致突变性，但可能具有致突变性。将ATCTP与标准药物氟康唑相比，对……的天冬氨酸蛋白酶（ID：2QZX）进行分子对接研究。与标准药物氟康唑（-5.6 kcal/mol）相比，化合物ATCTP具有更高的结合亲和力（-8.1 kcal/mol），氟康唑记录有4个传统氢键相互作用，而ATCTP与2QZX相互作用形成2个氢键。ATCTP还报告其结合亲和力为-7.2 kcal/mol，据报道超过了2QZX与氟康唑相互作用的亲和力（-5.7 kcal/mol）。ATCTP与羊毛甾醇14-α-脱甲基酶（5v5z）结合，结合亲和力为-9.7 kcal/mol，与该蛋白的活性位点氨基酸残基结合，而氟康唑与5v5z结合的亲和力为-8.0 kcal/mol。因此，建议ATCTP作为一种先导化合物，用于可能设计一种新的、更有效的抗念珠菌治疗化合物。
