Saleem Shahzad, Bibi Shabana, Yousafi Qudsia, Hassan Tehzeem, Khan Muhammad Saad, Hasan Mohammad Mehedi, Chopra Hitesh, Moustafa Mahmoud, Al-Shehri Mohammed, Khalid Mohammad, Kabra Atul
COMSATS University Islamabad, Sahiwal Campus, Sahiwal, Pakistan.
Department of Biological Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan.
Evid Based Complement Alternat Med. 2022 Jun 8;2022:7040547. doi: 10.1155/2022/7040547. eCollection 2022.
Diabetes mellitus (DM) is a very common metabolic disorder/disease. The deterioration of -cells by autoimmune system is the hallmark of this disease. Thioredoxin-Interacting Protein (TXNIP) is responsible for -cells degradation by T-cells in the pancreas. This protein had been declared a good drug target for controlling DM. Lots of side effects have been reported as a result of long-time consumption of conventional antidiabetic drugs. The development of new and effective drugs with the minimal side effects needs time. TXNIP was selected as a target for Computer-Aided Drug Design. The antidiabetic fungal metabolite compounds were selected from the literature. The compounds were screened for their drug-likeness properties by DruLiTo and DataWarior tools. Twenty-two drug-like fungal compounds were subjected to Quantitative Structure-Activity Relationship (QSAR) analysis by using CheS-Mapper 2.0. The lowest (0.01) activity cliff was found for three compounds: Pinazaphilone A, Pinazaphilone B, and Chermesinone A. The highest value for apol (81.76) was shown by Asperphenamate, while Albonoursin and Sterenin L showed highest score (40.66) for bpol. The lowest value (0.46) for fractional molecular frame (FMF) was calculated for Pinazaphilone A and Pinazaphilone B. TPSA for Pinazaphilone A and Pinazaphilone B was 130.51 Å. log < 5 was observed for all the twenty-two compounds. Molecular docking of fungal compounds with TXNIP was done by AutoDock Vina. The binding energy for complexes ranged between -9.2 and -4.6 kcal/mol. Four complexes, TXNIP-Pinazaphilone A, TXNIP-Pinazaphilone B, TXNIP-Asperphenamate, and TXNIP-Sterenin L, were selected for MD simulation to find out the best lead molecule. Only one complex, TXNIP-Pinazaphilone B, showed a stable conformation throughout the 80 ns run of MD simulation. Pinazaphilone B derived from the species fungi was selected as the lead molecule for development of antidiabetic drug having the least side effects.
糖尿病（DM）是一种非常常见的代谢紊乱/疾病。自身免疫系统对β细胞的破坏是这种疾病的标志。硫氧还蛋白相互作用蛋白（TXNIP）负责胰腺中T细胞对β细胞的降解。这种蛋白质已被宣布为控制糖尿病的良好药物靶点。长期服用传统抗糖尿病药物已报告有许多副作用。开发副作用最小的新型有效药物需要时间。TXNIP被选为计算机辅助药物设计的靶点。从文献中选择抗糖尿病真菌代谢物化合物。通过DruLiTo和DataWarior工具筛选这些化合物的类药性质。使用CheS-Mapper 2.0对22种类药真菌化合物进行定量构效关系（QSAR）分析。发现三种化合物：匹那扎菲隆A、匹那扎菲隆B和赭曲霉酮A的活性悬崖最低（0.01）。曲霉酸显示apol的最高值（81.76），而阿尔波诺菌素和硬脂菌素L显示bpol的最高得分（40.66）。计算得出匹那扎菲隆A和匹那扎菲隆B的分数分子框架（FMF）最低值（0.46）。匹那扎菲隆A和匹那扎菲隆B的拓扑极性表面积（TPSA）为130.51 Å。所有22种化合物的log P均<5。通过AutoDock Vina对真菌化合物与TXNIP进行分子对接。复合物的结合能在-9.2至-4.6 kcal/mol之间。选择四种复合物，TXNIP-匹那扎菲隆A、TXNIP-匹那扎菲隆B、TXNIP-曲霉酸和TXNIP-硬脂菌素L进行分子动力学（MD）模拟，以找出最佳先导分子。在80 ns的MD模拟运行中，只有一种复合物TXNIP-匹那扎菲隆B显示出稳定的构象。从真菌物种中提取的匹那扎菲隆B被选为开发副作用最小的抗糖尿病药物的先导分子。
