Multi-Fold Computational Analysis to Discover Novel Putative Inhibitors of Isethionate Sulfite-Lyase from IBilophila wadsworthia:/I Combating Colorectal Cancer and Inflammatory Bowel Diseases

Hydrogen sulfide (H[sub.2]S) has been produced by certain gut bacteria and associated with the development of inflammatory bowel disease (IBD) and colon cancer. H[sub.2]S is produced by these bacteria regulate the gut inflammation and cell proliferation. The resulted H[sub.2]S produced by an enzyme Isethionate sulfite-lyase (Isla) in the colonial Bilophila wadsworthia bacteria. Literature has suggested a potential association between Isla and cancer and the production of hydrogen sulfide (H[sub.2]S). Studies suggest that reducing the H[sub.2]S concentration by targeting Isla is a novel and potential therapeutic target for IBD and colon cancer. We apply structure-based drug-designing approaches for Isla and isolate six compounds from natural products and their synthetic derivatives having improved drug-like properties. The molecular dynamics approach was used to confirm the stability and affinity of the selected compounds. Our finding suggests that these compounds can be possible potential inhibitors for the Isla protein. 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 H[sub.2]S damages the colon’s mucous lining, which aids in the development of colorectal cancer. H[sub.2]S 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 tha