Multi-Fold Computational Analysis to Discover Novel Putative Inhibitors of Isethionate Sulfite-Lyase (Isla) from Bilophila wadsworthia: Combating Colorectal Cancer and Inflammatory Bowel Diseases
Open Access
- 30 January 2023
- Vol. 15 (3), 901
- https://doi.org/10.3390/cancers15030901
Abstract
A glycal radical enzyme called isethionate sulfite-lyase (Isla) breaks the C–S bond in isethionate to produce acetaldehyde and sulfite. This enzyme was found in the Gram-negative, colonial Bilophila wadsworthia bacteria. Sulfur dioxide, acetate, and ammonia are produced by the anaerobic respiration route from (sulfonate isethionate). Strong genotoxic H2S damages the colon’s mucous lining, which aids in the development of colorectal cancer. H2S production also contributes to inflammatory bowel diseases such as colitis. Here, we describe the structure-based drug designing for the Isla using an in-house database of naturally isolated compounds and synthetic derivatives. In structure-based drug discovery, a combination of methods was used, including molecular docking, pharmacokinetics properties evaluation, binding free energy calculations by the molecular mechanics/generalized born surface area (MM/GBSA) method, and protein structure dynamics exploration via molecular dynamic simulations, to retrieve novel and putative inhibitors for the Isla protein. Based on the docking score, six compounds show significant binding interaction with the Isla active site crucial residues and exhibit drug-like features, good absorption, distribution, metabolism, and excretion profile with no toxicity. The binding free energy reveals that these compounds have a strong affinity with the Isla. In addition, the molecular dynamics simulations reveal that these compounds substantially affect the protein structure dynamics. As per our knowledge, this study is the first attempt to discover Isla potential inhibitors. The compounds proposed in the study using a multi-fold computational technique may be verified in vitro as possible inhibitors of Isla and possess the potential for the future development of new medications that target Isla.Funding Information
- The Oman Research Council (BFP/RGP/EBR/22/021)
- Umm Al-Qura University (22UQU4331128DSR49)
This publication has 51 references indexed in Scilit:
- Human Intestinal Lumen and Mucosa-Associated Microbiota in Patients with Colorectal CancerPLOS ONE, 2012
- Microbial pathways in colonic sulfur metabolism and links with health and diseaseFrontiers in Physiology, 2012
- Genomic analysis identifies association of Fusobacterium with colorectal carcinomaGenome Research, 2011
- Fusobacterium nucleatum infection is prevalent in human colorectal carcinomaGenome Research, 2011
- Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteersThe ISME Journal, 2011
- Virtual screening using molecular simulationsProteins, 2011
- Assessing the Performance of the MM/PBSA and MM/GBSA Methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics SimulationsJournal of Chemical Information and Modeling, 2010
- Evidence That Hydrogen Sulfide Is a Genotoxic AgentMolecular Cancer Research, 2006
- Fast, efficient generation of high‐quality atomic charges. AM1‐BCC model: II. Parameterization and validationJournal of Computational Chemistry, 2002
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996