Multi-Fold Computational Analysis to Discover Novel Putative Inhibitors of Isethionate Sulfite-Lyase (Isla) from Bilophila wadsworthia: Combating Colorectal Cancer and Inflammatory Bowel Diseases
by
, , , ,
Muhammad Waqas
1,2,†
,
Sobia Ahsan Halim
1,†
,
Atta Ullah
1,3,
Assim Alaa Mohammed Ali
1,
Asaad Khalid
4,5
,
Ashraf N. Abdalla
6
,
Ajmal Khan
1,* and 
Ahmed Al-Harrasi
1,*
1
Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, P.O. Box 33, Nizwa 616, Oman
2
Department of Biotechnology and Genetic Engineering, Hazara University Mansehra, Mansehra 2100, Pakistan
3
Department of Zoology, Abdul Wali Khan University, Mardan 23200, Pakistan
4
Substance Abuse and Toxicology Research Center, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia
5
Medicinal and Aromatic Plants and Traditional Medicine Research Institute, National Center for Research, P.O. Box 2404, Khartoum 11111, Sudan
6
Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2023, 15(3), 901; https://doi.org/10.3390/cancers15030901
Submission received: 22 December 2022
/
Revised: 19 January 2023
/
Accepted: 29 January 2023
/
Published: 31 January 2023
(This article belongs to the Special Issue Advances in Anticancer Drugs and Pharmacotherapy of Cancer)
Simple Summary
Hydrogen sulfide (H2S) has been produced by certain gut bacteria and associated with the development of inflammatory bowel disease (IBD) and colon cancer. H2S is produced by these bacteria regulate the gut inflammation and cell proliferation. The resulted H2S 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 (H2S). Studies suggest that reducing the H2S 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.
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.
