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Published on: July 18, 2012
Target-based drug repurposing against Candida albicans-A computational modeling, docking, and molecular dynamic
Rashi Verma1,2, Dibyabhaba Pradhan3, Arnab Nayek4
1Department of Biosciences, Jamia Millia Islamia, New Delhi, India.
Abstract:
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.
Insights
Drug repurposing offers a strategy against multidrug-resistant Candida albicans. This study identified Arbutamine as a promising antifungal candidate targeting TRR1, with potential broad-spectrum activity against Candida species.
Area of Science:
- Computational biology and bioinformatics
- Drug discovery and development
- Mycology and infectious diseases
Background:
- Multidrug-resistant Candida albicans poses a global health threat, particularly in immunocompromised patients with invasive candidiasis.
- Drug repurposing is an effective strategy for rapid management of life-threatening fungal infections.
Purpose of the Study:
- To computationally evaluate Food and Drug Administration (FDA)-approved drugs for potential repurposing against drug targets of Candida albicans.
- To identify novel drug candidates and understand their binding mechanisms with key fungal targets.
Main Methods:
- In silico modeling, refinement, and structural integrity evaluation of drug targets TRR1, TOM40, and YHB1 using PROCHECK, ERRAT, and PROSA.
- High-throughput virtual screening of 8815 FDA-approved drugs, followed by interaction and energy profile analysis.
- Molecular dynamic simulations, MM-PBSA, RMSD, radius of gyration, and Principal Component Analysis (PCA) to assess drug-target complex stability and interactions.
Main Results:
- Arbutamine (DB01102), Hydroxychloroquine (DB01611), and Carindacillin (DB09319) showed significant binding affinity to TRR1, TOM40, and YHB1, respectively.
- Molecular dynamics simulations identified crucial residues (e.g., Gln45, Thr119, Asp288 in TRR1) for stable drug-target interactions.
- Arbutamine-TRR1 complex demonstrated superior stability based on MM-PBSA, RMSD, and radius of gyration analyses, supported by PCA. Conserved TRR1 regions suggest Arbutamine's potential efficacy against multiple Candida species.
Conclusions:
- Arbutamine is a prioritized drug candidate for repurposing against Candida albicans, exhibiting strong binding and stability with the TRR1 target.
- The study provides valuable insights into developing novel antifungal strategies through drug repurposing and computational approaches.
- Experimental validation is essential to confirm the efficacy of Arbutamine against invasive candidiasis.
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