环氧合酶-2(COX-2)是负责花生四烯酸转化为前列腺素的关键酶,显示促炎特性,因此,它是开发抗炎药的潜在靶蛋白。在这项研究中,化学和生物信息学方法已被用于发现一种新的有效穿心莲内酯(AGP)类似物作为COX-2抑制剂,其药理学特性优于阿司匹林和罗非考昔(对照).选择完整氨基酸测序的人Alpha折叠(AF)COX-2蛋白(604AA),并验证其相对于报道的COX-2蛋白结构的准确性(PDBID:5F19,5KIR,5F1A,5IKQ和1V0X)随后进行多序列比对分析以建立序列保守性。基于结合能评分(<-8.0kcal/mol),针对AF-COX-2蛋白的237个AGP类似物的系统虚拟筛选产生22个前导化合物。通过分子对接分析进一步筛选出7种类似物,并进一步研究用于ADMET预测,配体效率指标计算,量子力学分析,MD模拟,静电势能(EPE)对接模拟,MM/GBSA。深入分析发现AGP类似物A3(3-[2-[(1R,4aR,5R,6R,8aR)-6-羟基-5,6,8a-三甲基-2-亚甲基-3,4,4a,5,7,8-六氢-1H-萘-1-基]亚乙基]-4-羟基氧戊环-2-酮)与AF-COX-2形成最稳定的络合物,其RMSD值最小(0.37±0.03nm),大量的氢键(蛋白质配体H键=11,蛋白质H键=525),最低EPE评分(-53.81kcal/mol),以及模拟前后的最低MM-GBSA(-55.37和-56.25kcal/mol,分别)与其他类似物和对照相比的值。因此,我们建议,鉴定的A3AGP类似物可以通过抑制COX-2被开发为有前途的基于植物的抗炎药。
Cyclooxygenase-2 (COX-2) is the key enzyme responsible for the conversion of arachidonic acid to prostaglandins that display pro-inflammatory properties and thus, it is a potential target protein to develop anti-inflammatory drugs. In this study, chemical and bio-informatics approaches have been employed to find a novel potent andrographolide (AGP) analog as a COX-2 inhibitor having better pharmacological properties than aspirin and rofecoxib (controls). The full amino acid sequenced human Alpha fold (AF) COX-2 protein (604AA) was selected and validated for its accuracy against the reported COX-2 protein structures (PDB ID: 5F19, 5KIR, 5F1A, 5IKQ and 1V0X) followed by multiple sequence alignment analysis to establish the sequence conservation. The systematic virtual screening of 237 AGP analogs against AF-COX-2 protein yielded 22 lead compounds based on the binding energy score (< - 8.0 kcal/mol). These were further screened out to 7 analogs by molecular docking analysis and investigated further for ADMET prediction, ligand efficiency metrics calculations, quantum mechanical analysis, MD simulation, electrostatic potential energy (EPE) docking simulation, and MM/GBSA. In-depth analysis revealed that AGP analog A3 (3-[2-[(1R,4aR,5R,6R,8aR)-6-hydroxy-5,6,8a-trimethyl-2-methylidene-3,4,4a,5,7,8-hexahydro-1H-naphthalen-1-yl]ethylidene]-4-hydroxyoxolan-2-one) forms the most stable complex with the AF-COX-2 showing the least RMSD value (0.37 ± 0.03 nm), a good number of hydrogen bonds (protein-ligand H-bond = 11, and protein H-bond = 525), minimum EPE score (- 53.81 kcal/mol), and lowest MM-GBSA before and after simulation (- 55.37 and - 56.25 kcal/mol, respectively) value compared to other analogs and controls. Thus, we suggest that the identified A3 AGP analog could be developed as a promising plant-based anti-inflammatory drug by inhibiting COX-2.