Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
Biomedical Informatics Centre, Indian Council of Medical Research, New Delhi, India.
J Cell Biochem. 2022 Feb;123(2):289-305. doi: 10.1002/jcb.30163. Epub 2021 Oct 21.
The emergence of multidrug-resistant strains of Candida albicans has become a global threat mostly due to co-infection with immune-compromised patients leading to invasive candidiasis. The life-threatening form of the disease can be managed quickly and effectively by drug repurposing. Thus, the study used in silico approaches to evaluate Food and Drug Administration (FDA) approved drugs against three drug targets-TRR1, TOM40, and YHB1. The tertiary structures of three drug targets were modeled, refined, and evaluated for their structural integrity based on PROCHECK, ERRAT, and PROSA. High-throughput virtual screening of FDA-approved drugs (8815), interaction analysis, and energy profiles had revealed that DB01102 (Arbutamine), DB01611 (Hydroxychloroquine), and DB09319 (Carindacillin) exhibited better binding affinity with TRR1, TOM40, and YHB1, respectively. Notably, the molecular dynamic simulation explored that Gln45, Thr119, and Asp288 of TRR1; Thr107 and Ser121 of TOM40; Arg193, Glu213, and Ser228 of YHB1 are crucial residues for stable drug-target interaction. Additionally, it also prioritized Arbutamine-TRR1 as the best drug-target complex based on MM-PBSA (-52.72 kcal/mol), RMSD (2.43 Å), and radius of gyration (-21.49 Å) analysis. In-depth, PCA results supported the findings of molecular dynamic simulations. Interestingly, the conserved region (>70%) among the TRR1 sequences from pathogenic Candida species indicated the effectiveness of Arbutamine against multiple species of Candida as well. Thus, the study dispenses new insight and enriches the understanding of developing an advanced technique to consider potential antifungals against C. albicans. Nonetheless, a detailed experimental validation is needed to investigate the efficacy of Arbutamin against life-threatening candidiasis.
白色念珠菌多药耐药株的出现已成为全球性威胁，主要是由于与免疫功能低下的患者合并感染导致侵袭性念珠菌病。通过药物再利用可以快速有效地治疗这种危及生命的疾病。因此，该研究使用计算机模拟方法评估了美国食品和药物管理局 (FDA) 批准的三种药物靶点 TRR1、TOM40 和 YHB1 的药物。对三种药物靶点的三级结构进行建模、精修和评估，以根据 PROCHECK、ERRAT 和 PROSA 评估其结构完整性。高通量虚拟筛选 FDA 批准的药物（8815 种）、相互作用分析和能量谱揭示了 DB01102（熊果苷）、DB01611（羟氯喹）和 DB09319（卡茚西林）分别与 TRR1、TOM40 和 YHB1 具有更好的结合亲和力。值得注意的是，分子动力学模拟表明，TRR1 的 Gln45、Thr119 和 Asp288；TOM40 的 Thr107 和 Ser121；YHB1 的 Arg193、Glu213 和 Ser228 是稳定药物-靶标相互作用的关键残基。此外，它还根据 MM-PBSA（-52.72 kcal/mol）、RMSD（2.43 Å）和回转半径（-21.49 Å）分析，将熊果苷-TRR1 优先作为最佳药物-靶标复合物。深入的 PCA 结果支持分子动力学模拟的结果。有趣的是，来自致病性念珠菌种的 TRR1 序列中的保守区域（>70%）表明熊果苷对多种念珠菌种有效。因此，该研究为开发针对白色念珠菌的新技术提供了新的见解，并丰富了对开发潜在抗真菌药物的理解。然而，需要进行详细的实验验证来研究熊果苷对抗危及生命的念珠菌病的疗效。
