{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:03:05Z","timestamp":1790758985582,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T00:00:00Z","timestamp":1675123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Oman Research Council","award":["BFP\/RGP\/EBR\/22\/021"],"award-info":[{"award-number":["BFP\/RGP\/EBR\/22\/021"]}]},{"name":"The Oman Research Council","award":["22UQU4331128DSR49"],"award-info":[{"award-number":["22UQU4331128DSR49"]}]},{"name":"Umm Al-Qura University","award":["BFP\/RGP\/EBR\/22\/021"],"award-info":[{"award-number":["BFP\/RGP\/EBR\/22\/021"]}]},{"name":"Umm Al-Qura University","award":["22UQU4331128DSR49"],"award-info":[{"award-number":["22UQU4331128DSR49"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>A glycal radical enzyme called isethionate sulfite-lyase (Isla) breaks the C\u2013S 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/cancers15030901","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T05:33:53Z","timestamp":1675229633000},"page":"901","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Multi-Fold Computational Analysis to Discover Novel Putative Inhibitors of Isethionate Sulfite-Lyase (Isla) from Bilophila wadsworthia: Combating Colorectal Cancer and Inflammatory Bowel Diseases"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6115-9689","authenticated-orcid":false,"given":"Muhammad","family":"Waqas","sequence":"first","affiliation":[{"name":"Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, P.O. Box 33, Nizwa 616, Oman"},{"name":"Department of Biotechnology and Genetic Engineering, Hazara University Mansehra, Mansehra 2100, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8526-7799","authenticated-orcid":false,"given":"Sobia Ahsan","family":"Halim","sequence":"additional","affiliation":[{"name":"Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, P.O. Box 33, Nizwa 616, Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atta","family":"Ullah","sequence":"additional","affiliation":[{"name":"Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, P.O. Box 33, Nizwa 616, Oman"},{"name":"Department of Zoology, Abdul Wali Khan University, Mardan 23200, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Assim Alaa Mohammed","family":"Ali","sequence":"additional","affiliation":[{"name":"Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, P.O. Box 33, Nizwa 616, Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8734-2588","authenticated-orcid":false,"given":"Asaad","family":"Khalid","sequence":"additional","affiliation":[{"name":"Substance Abuse and Toxicology Research Center, Jazan University, P.O. Box 114, Jazan 45142, Saudi Arabia"},{"name":"Medicinal and Aromatic Plants and Traditional Medicine Research Institute, National Center for Research, P.O. Box 2404, Khartoum 11111, Sudan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4770-9319","authenticated-orcid":false,"given":"Ashraf N.","family":"Abdalla","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajmal","family":"Khan","sequence":"additional","affiliation":[{"name":"Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, P.O. Box 33, Nizwa 616, Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0815-5942","authenticated-orcid":false,"given":"Ahmed","family":"Al-Harrasi","sequence":"additional","affiliation":[{"name":"Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, P.O. Box 33, Nizwa 616, Oman"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1093\/clinids\/18.6.1023","article-title":"Bilophila wadsworthia bacteremia in a patient with gangrenous appendicitis","volume":"18","author":"Bernard","year":"1994","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1006\/anae.1997.0075","article-title":"Bilophila wadsworthia: A unique Gram-negative anaerobic rod","volume":"3","author":"Baron","year":"1997","journal-title":"Anaerobe"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1128\/jcm.30.9.2502-2503.1992","article-title":"Bilophila wadsworthia bacteremia in two patients with hepatic abscesses","volume":"30","author":"Kasten","year":"1992","journal-title":"J. Clin. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10038","DOI":"10.1073\/pnas.1507645112","article-title":"Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon","volume":"112","author":"Ijssennagger","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.molmed.2016.01.002","article-title":"Sulfide as a mucus barrier-breaker in inflammatory bowel disease?","volume":"22","author":"Ijssennagger","year":"2016","journal-title":"Trends Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/nature13398","article-title":"High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity","volume":"514","author":"Schulz","year":"2014","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.chom.2013.07.007","article-title":"Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment","volume":"14","author":"Kostic","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20","DOI":"10.3389\/fmicb.2015.00020","article-title":"Microbiota disbiosis is associated with colorectal cancer","volume":"6","author":"Gao","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1101\/gr.126573.111","article-title":"Genomic analysis identifies association of Fusobacterium with colorectal carcinoma","volume":"22","author":"Kostic","year":"2012","journal-title":"Genome Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/2049-2618-1-16","article-title":"Co-occurrence of anaerobic bacteria in colorectal carcinomas","volume":"1","author":"Warren","year":"2013","journal-title":"Microbiome"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/ismej.2011.109","article-title":"Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers","volume":"6","author":"Wang","year":"2012","journal-title":"ISME J."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chen, W., Liu, F., Ling, Z., Tong, X., and Xiang, C. (2012). Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039743"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1101\/gr.126516.111","article-title":"Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma","volume":"22","author":"Castellarin","year":"2012","journal-title":"Genome Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"766","DOI":"10.15252\/msb.20145645","article-title":"Potential of fecal microbiota for early-stage detection of colorectal cancer","volume":"10","author":"Zeller","year":"2014","journal-title":"Mol. Syst. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1158\/1940-6207.CAPR-14-0129","article-title":"The human gut microbiome as a screening tool for colorectal cancer","volume":"7","author":"Zackular","year":"2014","journal-title":"Cancer Prev. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6342","DOI":"10.1038\/ncomms7342","article-title":"Fat, fibre and cancer risk in African Americans and rural Africans","volume":"6","author":"Li","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1096\/fj.02-0883fje","article-title":"Hydrogen sulfide induces serum-independent cell cycle entry in nontransformed rat intestinal epithelial cells","volume":"17","author":"Deplancke","year":"2003","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1158\/1541-7786.MCR-05-0126","article-title":"Evidence that hydrogen sulfide is a genotoxic agent","volume":"4","author":"Wagner","year":"2006","journal-title":"Mol. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1158\/1541-7786.MCR-06-0439","article-title":"Hydrogen sulfide induces direct radical-associated DNA damage","volume":"5","author":"Wagner","year":"2007","journal-title":"Mol. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1016\/j.chembiol.2021.03.001","article-title":"Molecular basis of C-S bond cleavage in the glycyl radical enzyme isethionate sulfite-lyase","volume":"28","author":"Dawson","year":"2021","journal-title":"Cell Chem. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3171","DOI":"10.1073\/pnas.1815661116","article-title":"A glycyl radical enzyme enables hydrogen sulfide production by the human intestinal bacterium Bilophila wadsworthia","volume":"116","author":"Peck","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"448","DOI":"10.3389\/fphys.2012.00448","article-title":"Microbial pathways in colonic sulfur metabolism and links with health and disease","volume":"3","author":"Carbonero","year":"2012","journal-title":"Front. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"866","DOI":"10.3390\/microorganisms3040866","article-title":"Hydrogen Sulfide in Physiology and Diseases of the Digestive Tract","volume":"3","author":"Singh","year":"2015","journal-title":"Microorganisms"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1111\/j.1574-6941.1998.tb00487.x","article-title":"Enumeration of amino acid fermenting bacteria in the human large intestine: Effects of pH and starch on peptide metabolism and dissimilation of amino acids","volume":"25","author":"Smith","year":"1998","journal-title":"FEMS Microbiol. Ecol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.7554\/eLife.51420","article-title":"Molecular basis for catabolism of the abundant metabolite trans-4-hydroxy-l-proline by a microbial glycyl radical enzyme","volume":"9","author":"Backman","year":"2020","journal-title":"eLife"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1038\/s41467-019-09618-8","article-title":"Radical-mediated C-S bond cleavage in C2 sulfonate degradation by anaerobic bacteria","volume":"10","author":"Xing","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_27","first-page":"262","article-title":"Taurine: A conditionally essential amino acid in humans? An overview in health and disease","volume":"17","author":"Lourenco","year":"2002","journal-title":"Nutr. Hosp."},{"key":"ref_28","first-page":"2673","article-title":"Taurine: A \u201cvery essential\u201d amino acid","volume":"18","author":"Ripps","year":"2012","journal-title":"Mol. Vis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"105743","DOI":"10.1016\/j.compbiomed.2022.105743","article-title":"Discovering novel inhibitors of P2Y(12) receptor using structure-based virtual screening, molecular dynamics simulation and MMPBSA approaches","volume":"147","author":"Halim","year":"2022","journal-title":"Comput. Biol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.ijbiomac.2022.06.001","article-title":"Identification of novel prolyl oligopeptidase inhibitors from resin of Boswellia papyrifera (Del.) Hochst. and their mechanism: Virtual and biochemical studies","volume":"213","author":"Khan","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Asmari, M., Waqas, M., Ibrahim, A.E., Halim, S.A., Khan, A., Al-Harrasi, A., Watzig, H., and El Deeb, S. (2022). Microscale Thermophoresis and Molecular Modelling to Explore the Chelating Drug Transportation in the Milk to Infant. Molecules, 27.","DOI":"10.3390\/molecules27144604"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Halim, S.A., Waqas, M., Khan, A., and Al-Harrasi, A. (2021). In silico prediction of novel inhibitors of SARS-CoV-2 main protease through structure-based virtual screening and molecular dynamic simulation. Pharmaceuticals, 14.","DOI":"10.3390\/ph14090896"},{"key":"ref_33","unstructured":"Chemical Computing Group ULC (2022). Molecular Operating Environment (MOE), Chemical Computing Group ULC. version 2022.02."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/BF00124456","article-title":"MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry","volume":"9","author":"Gerber","year":"1995","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_37","unstructured":"Case, D., Aktulga, H., Belfon, K., Ben-Shalom, I., Berryman, J., Brozell, S., Cerutti, D., Cheatham, T., Cisneros, G., and Cruzeiro, V. (2022). Amber2022, University of California. version 2022."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1021\/acs.jctc.9b00591","article-title":"ff19SB: Amino-Acid-Specific Protein Backbone Parameters Trained against Quantum Mechanics Energy Surfaces in Solution","volume":"16","author":"Tian","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1021\/acs.jctc.8b01039","article-title":"Assessment of GAFF2 and OPLS-AA General Force Fields in Combination with the Water Models TIP3P, SPCE, and OPC3 for the Solvation Free Energy of Druglike Organic Molecules","volume":"15","author":"Vassetti","year":"2019","journal-title":"J. Chem. Theory Comput."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1002\/(SICI)1096-987X(20000130)21:2<132::AID-JCC5>3.0.CO;2-P","article-title":"Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method","volume":"21","author":"Jakalian","year":"2000","journal-title":"J. Comput. Chem."},{"key":"ref_41","first-page":"U403","article-title":"Antechamber: An accessory software package for molecular mechanical calculations","volume":"222","author":"Wang","year":"2001","journal-title":"J. Am. Chem. Soc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3878","DOI":"10.1021\/ct400314y","article-title":"Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald","volume":"9","author":"Gotz","year":"2013","journal-title":"J. Chem. Theory Comput."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1063\/1.2820230","article-title":"Numerical recipes: The art of scientific computing","volume":"40","author":"Press","year":"1987","journal-title":"Phys. Today"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1021\/ct800573m","article-title":"Bad Seeds Sprout Perilous Dynamics: Stochastic Thermostat Induced Trajectory Synchronization in Biomolecules","volume":"5","author":"Sindhikara","year":"2009","journal-title":"J. Chem. Theory Comput."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1002\/1096-987X(20010415)22:5<501::AID-JCC1021>3.0.CO;2-V","article-title":"A fast SHAKE algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations","volume":"22","year":"2001","journal-title":"J. Comput. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1021\/ct400341p","article-title":"PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data","volume":"9","author":"Roe","year":"2013","journal-title":"J. Chem. Theory Comput."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1103\/PhysRevLett.80.2733","article-title":"Vibrational dynamics of folded proteins: Significance of slow and fast motions in relation to function and stability","volume":"80","author":"Bahar","year":"1998","journal-title":"Phys. Rev. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Wen, J., Scoles, D.R., and Facelli, J.C. (2017). Molecular dynamics analysis of the aggregation propensity of polyglutamine segments. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178333"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1021\/ci100275a","article-title":"Assessing the performance of the MM\/PBSA and MM\/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations","volume":"51","author":"Hou","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1002\/prot.23018","article-title":"Virtual screening using molecular simulations","volume":"79","author":"Yang","year":"2011","journal-title":"Proteins"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1021\/ar000033j","article-title":"Calculating structures and free energies of complex molecules: Combining molecular mechanics and continuum models","volume":"33","author":"Kollman","year":"2000","journal-title":"Acc. Chem. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_53","unstructured":"Schr\u00f6dinger, L. (2018). The PyMOL Molecular Graphics System, Schr\u00f6dinger, LLC. version 1.8."},{"key":"ref_54","unstructured":"Community, B.O. (2023, January 28). Blender\u2014A 3D Modelling and Rendering Package. Available online: https:\/\/www.blender.org\/."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/3\/901\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:20:20Z","timestamp":1760120420000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/3\/901"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,31]]},"references-count":54,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["cancers15030901"],"URL":"https:\/\/doi.org\/10.3390\/cancers15030901","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,31]]}}}