{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T20:11:21Z","timestamp":1788120681146,"version":"build-2803163510"},"reference-count":104,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2018,6,27]],"date-time":"2018-06-27T00:00:00Z","timestamp":1530057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Buruli ulcer (BU) is caused by Mycobacterium ulcerans and is predominant in both tropical and subtropical regions. The neglected debilitating disease is characterized by chronic necrotizing skin lesions attributed to a mycolactone, which is a macrolide toxin secreted by M. ulcerans. The preferred treatment is surgical excision of the lesions followed by a prolonged combination antibiotic therapy using existing drugs such as rifampicin and streptomycin or clarithromycin. These antibiotics appear not to be adequately potent and efficacious against persistent and late stage ulcers. In addition, emerging drug resistance to treatment poses great challenges. There is a need to identify novel natural product-derived lead compounds, which are potent and efficacious for the treatment of Buruli ulcer. Natural products present a rich diversity of chemical compounds with proven activity against various infectious diseases, and therefore, are considered in this study. This study sought to computationally predict natural product-derived lead compounds with the potential to be developed further into potent drugs with better therapeutic efficacy than the existing anti-buruli ulcer compounds. The three-dimensional (3D) structure of Isocitrate lyase (ICL) of Mycobacterium ulcerans was generated using homology modeling and was further scrutinized with molecular dynamics simulations. A library consisting of 885 compounds retrieved from the AfroDb database was virtually screened against the validated ICL model using AutoDock Vina. AfroDb is a compendium of \u201cdrug-like\u201d and structurally diverse 3D structures of natural products originating from different geographical regions in Africa. The molecular docking with the ICL model was validated by computing a Receiver Operating Characteristic (ROC) curve with a reasonably good Area Under the Curve (AUC) value of 0.89375. Twenty hit compounds, which docked firmly within the active site pocket of the ICL receptor, were assessed via in silico bioactivity and pharmacological profiling. The three compounds, which emerged as potential novel leads, comprise ZINC38143792 (Euscaphic acid), ZINC95485880, and ZINC95486305 with reasonable binding energies (high affinity) of \u22128.6, \u22128.6, and \u22128.8 kcal\/mol, respectively. Euscaphic acid has been reported to show minimal inhibition against a drug-sensitive strain of M. tuberculosis. The other two leads were both predicted to possess dermatological activity while one was antibacterial. The leads have shown promising results pertaining to efficacy, toxicity, pharmacokinetic, and safety. These leads can be experimentally characterized to assess their anti-mycobacterial activity and their scaffolds may serve as rich skeletons for developing anti-buruli ulcer drugs.<\/jats:p>","DOI":"10.3390\/molecules23071550","type":"journal-article","created":{"date-parts":[[2018,6,27]],"date-time":"2018-06-27T11:02:05Z","timestamp":1530097325000},"page":"1550","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1093-1517","authenticated-orcid":false,"given":"Samuel K.","family":"Kwofie","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 77, Legon, Accra, Ghana"},{"name":"Department of Biochemistry, Cell and Molecular Biology, West African Center for Cell Biology and Infectious Pathogens, University of Ghana, P. O. Box LG 77, Legon, Accra, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bismark","family":"Dankwa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 77, Legon, Accra, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel A.","family":"Odame","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 77, Legon, Accra, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2980-1392","authenticated-orcid":false,"given":"Francis E.","family":"Agamah","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 77, Legon, Accra, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lady P. A.","family":"Doe","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 77, Legon, Accra, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Teye","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 77, Legon, Accra, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odame","family":"Agyapong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 77, Legon, Accra, Ghana"},{"name":"Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, P. O. Box LG 77, Legon, Accra, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3822-7940","authenticated-orcid":false,"suffix":"III","given":"Whelton A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Chemistry &amp; Physics, College of Science and Technology, Lincoln University, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Mosi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cell and Molecular Biology, West African Center for Cell Biology and Infectious Pathogens, University of Ghana, P. O. Box LG 77, Legon, Accra, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, P. O. Box LG 77, Legon, Accra, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6299","DOI":"10.1128\/IAI.73.10.6299-6310.2005","article-title":"Infection with Mycobacterium ulcerans Induces Persistent Inflammatory Responses in Mice","volume":"73","author":"Oliveira","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.4314\/gmj.v45i1.68920","article-title":"In the case of transmission of Mycobacterium ulcerans in buruli ulcer disease Acanthamoeba species stand accused","volume":"45","author":"Wilson","year":"2011","journal-title":"Ghana Med. J."},{"key":"ref_3","unstructured":"Le\u00e3o, S.C., Romano, M.I., and Jesus, M. (2018, May 16). Tuberculosis, Leprosy, and Other Mycobacterioses, Bioinformatics in Tropical Disease Research: A Practical and Case-Study Approach, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK6820\/."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4623","DOI":"10.1128\/AEM.68.9.4623-4628.2002","article-title":"Aquatic insects as a vector for Mycobacterium ulcerans","volume":"68","author":"Marsollier","year":"2002","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Marsollier, L., Deniaux, E., Brodin, P., Marot, A., Wondje, C.M., Saint-Andr\u00e9, J.-P., Chauty, A., Johnson, C., Tekaia, F., and Yeramian, E. (2007). Protection against Mycobacterium ulcerans Lesion Development by Exposure to Aquatic Insect Saliva. PLoS Med., 4.","DOI":"10.1371\/journal.pmed.0040064"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Merritt, R.W., Walker, E.D., Small, P.L.C., Wallace, J.R., Johnson, P.D.R., Benbow, M.E., and Boakye, D.A. (2010). Ecology and transmission of Buruli ulcer disease: A systematic review. PLoS Negl. Trop. Dis., 4.","DOI":"10.1371\/journal.pntd.0000911"},{"key":"ref_7","unstructured":"World Health Organization (WHO) (2012). Treatment of Mycobacterium Ulcerans Disease (Buruli Ulcer), WHO."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Azumah, B.K., Addo, P.G., Dodoo, A., Awandare, G., Mosi, L., Boakye, D.A., and Wilson, M.D. (2017). Experimental demonstration of the possible role of Acanthamoeba polyphaga in the infection and disease progression in Buruli Ulcer (BU) using ICR mice. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172843"},{"key":"ref_9","unstructured":"WHO (2017). Buruli Ulcer, WHO."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1177\/1534734615599653","article-title":"The Buruli Ulcer","volume":"14","author":"Kumar","year":"2015","journal-title":"Int. J. Low. Extrem. Wounds"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Klis, S., Stienstra, Y., Phillips, R.O., Abass, K.M., Tuah, W., and van der Werf, T.S. (2014). Long Term Streptomycin Toxicity in the Treatment of Buruli Ulcer: Follow-up of Participants in the BURULICO Drug Trial. PLoS Negl. Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0002739"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Yeboah-Manu, D., Kpeli, G.S., Ruf, M.-T., Asan-Ampah, K., Quenin-Fosu, K., Owusu-Mireku, E., Paintsil, A., Lamptey, I., Anku, B., and Kwakye-Maclean, C. (2013). Secondary bacterial infections of buruli ulcer lesions before and after chemotherapy with streptomycin and rifampicin. PLoS Negl. Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002191"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Gordon, C.L., Buntine, J.A., Hayman, J.A., Lavender, C.J., Fyfe, J.A.M., Hosking, P., Starr, M., and Johnson, P.D.R. (2010). All-Oral Antibiotic Treatment for Buruli Ulcer: A Report of Four Patients. PLoS Negl. Trop. Dis., 4.","DOI":"10.1371\/journal.pntd.0000770"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1128\/AAC.00052-06","article-title":"In Vitro and In Vivo Activities of Rifampin, Streptomycin, Amikacin, Moxifloxacin, R207910, Linezolid, and PA-824 against Mycobacterium ulcerans","volume":"50","author":"Ji","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.1128\/AAC.00730-07","article-title":"Orally administered combined regimens for treatment of Mycobacterium ulcerans infection in mice","volume":"51","author":"Ji","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3132","DOI":"10.1128\/AAC.02658-15","article-title":"Comparative Study of Activities of a Diverse Set of Antimycobacterial Agents against Mycobacterium tuberculosis and Mycobacterium ulcerans","volume":"60","author":"Scherr","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.vascn.2015.03.001","article-title":"Methods used in preclinical assessment of anti-Buruli ulcer agents: A global perspective","volume":"73","author":"Tsouh","year":"2015","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_18","unstructured":"(2018, June 15). Buruli Ulcer (Mycobacterium ulcerans Infection). Available online: http:\/\/www.who.int\/en\/news-room\/fact-sheets\/detail\/buruli-ulcer-(mycobacterium-ulcerans-infection."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Johnson, P.D.R., Stinear, T., Small, P.L.C., Pluschke, G., Merritt, R.W., Portaels, F., Huygen, K., Hayman, J.A., and Asiedu, K. (2005). Buruli Ulcer (M. ulcerans Infection): New Insights, New Hope for Disease Control. PLoS Med., 2.","DOI":"10.1371\/journal.pmed.0020173"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10","DOI":"10.4103\/0974-8520.100295","article-title":"Drug discovery from plant sources: An integrated approach","volume":"33","author":"Katiyar","year":"2012","journal-title":"Ayu"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"127","DOI":"10.2174\/156802610790232251","article-title":"Successful Applications of Computer Aided Drug Discovery: Moving Drugs from Concept to the Clinic","volume":"10","author":"Talele","year":"2010","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhang, G., Guo, S., Cui, H., and Qi, J. (2018). Virtual Screening of Small Molecular Inhibitors against DprE1. Molecules, 23.","DOI":"10.3390\/molecules23030524"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.13005\/ojc\/290423","article-title":"Virtual Screening against Mycobacterium tuberculosis Lipoate Protein Ligase B (MtbLipB) and In Silico ADMET Evaluation of Top Hits","volume":"29","author":"Billones","year":"2013","journal-title":"Orient. J. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.jmgm.2008.08.005","article-title":"Virtual screening against Mycobacterium tuberculosis dihydrofolate reductase: Suggested workflow for compound prioritization using structure interaction fingerprints","volume":"27","author":"Kumar","year":"2008","journal-title":"J. Mol. Graph. Model."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/35021074","article-title":"Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase","volume":"406","author":"McKinney","year":"2000","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3166","DOI":"10.1099\/mic.0.030858-0","article-title":"Major roles of isocitrate lyase and malate synthase in bacterial and fungal pathogenesis","volume":"155","author":"Dunn","year":"2009","journal-title":"Microbiology"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lee, Y.-V., Wahab, H.A., and Choong, Y.S. (2015). Potential inhibitors for isocitrate lyase of Mycobacterium tuberculosis and non-M. tuberculosis: A summary. Biomed. Res. Int., 2015.","DOI":"10.1155\/2015\/895453"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.bbrc.2015.11.095","article-title":"Predicting unintended effects of drugs based on off-target tissue effects","volume":"469","author":"Kim","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chartier, M., Morency, L.-P., Zylber, M.I., and Najmanovich, R.J. (2017). Large-scale detection of drug off-targets: Hypotheses for drug repurposing and understanding side-effects. BMC Pharmacol. Toxicol., 18.","DOI":"10.1186\/s40360-017-0128-7"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chang, R.L., Xie, L., Xie, L., Bourne, P.E., and Palsson, B.\u00d8. (2010). Drug off-target effects predicted using structural analysis in the context of a metabolic network model. PLoS Comput. Biol., 6.","DOI":"10.1371\/journal.pcbi.1000938"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Butt, A.M., Nasrullah, I., Tahir, S., and Tong, Y. (2012). Comparative Genomics Analysis of Mycobacterium ulcerans for the Identification of Putative Essential Genes and Therapeutic Candidates. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0043080"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ntie-Kang, F., Zofou, D., Babiaka, S.B., Meudom, R., Scharfe, M., Lifongo, L.L., Mbah, J.A., Mbaze, L.M., Sippl, W., and Efange, S.M.N. (2013). AfroDb: A Select Highly Potent and Diverse Natural Product Library from African Medicinal Plants. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078085"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.micres.2013.12.009","article-title":"Exploring the potential of endophytes from medicinal plants as sources of antimycobacterial compounds","volume":"169","author":"Alvin","year":"2014","journal-title":"Microbiol. Res."},{"key":"ref_34","unstructured":"Dankwa, B., and Kwofie, K.S. (2017, January 6\u20137). In Silico Prediction of Potential Natural Product-Derived Lead Compounds for the Treatment of Buruli Ulcer. Proceedings of the Waccbip Research Conference, Legon, Accra."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"D30","DOI":"10.1093\/nar\/gku1216","article-title":"GenBank","volume":"43","author":"Benson","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_36","first-page":"D271","article-title":"The RCSB protein data bank: Integrative view of protein, gene and 3D structural information","volume":"45","author":"Rose","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D345","DOI":"10.1093\/nar\/gku1214","article-title":"The RCSB Protein Data Bank: Views of structural biology for basic and applied research and education","volume":"43","author":"Rose","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"W5","DOI":"10.1093\/nar\/gkn201","article-title":"NCBI BLAST: A better web interface","volume":"36","author":"Johnson","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"Altschul","year":"1990","journal-title":"J. Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"W252","DOI":"10.1093\/nar\/gku340","article-title":"SWISS-MODEL: Modelling protein tertiary and quaternary structure using evolutionary information","volume":"42","author":"Biasini","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Eswar, N., Webb, B., Marti-Renom, M.A., Madhusudhan, M.S., Eramian, D., Shen, M., Pieper, U., and Sali, A. (2007). Comparative Protein Structure Modeling Using MODELLER. Curr. Protoc. Protein Sci., 50.","DOI":"10.1002\/0471140864.ps0209s50"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1110\/ps.062416606","article-title":"Statistical potential for assessment and prediction of protein structures","volume":"15","author":"Shen","year":"2006","journal-title":"Protein Sci."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Webb, B., and Sali, A. (2016). Comparative protein structure modeling using MODELLER. Current Protocols in Bioinformatics, John Wiley & Sons, Inc.","DOI":"10.1002\/cpbi.3"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/978-1-60761-842-3_6","article-title":"Template-Based Protein Structure Modeling","volume":"Volume 673","author":"Fiser","year":"2010","journal-title":"Methods in Molecular Biology"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Hasan, M.A., Alauddin, S.M., Al Amin, M., Nur, S.M., and Mannan, A. (2014). In silico molecular characterization of cysteine protease YopT from Yersinia pestis by homology modeling and binding site identification. Drug Target Insights.","DOI":"10.33393\/dti.2014.1351"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1016\/j.bpj.2011.10.024","article-title":"Improving the Physical Realism and Structural Accuracy of Protein Models by a Two-Step Atomic-Level Energy Minimization","volume":"101","author":"Xu","year":"2011","journal-title":"Biophys. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_48","unstructured":"Bekker, H., Berendsen, H., Dijkstra, E., Achterop, S., Vondrumen, R., Vanderspoel, D., Sijbers, A., Keegstra, H., and Renardus, M. (1993). Gromacs\u2014A Parallel Computer for Molecular-Dynamics Simulations, World Scientific Publishing."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: Fast, flexible, and free","volume":"26","author":"Lindahl","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1093\/bioinformatics\/btg362","article-title":"ModLoop: Automated modeling of loops in protein structures","volume":"19","author":"Fiser","year":"2003","journal-title":"Bioinformatics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"W407","DOI":"10.1093\/nar\/gkm290","article-title":"ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins","volume":"35","author":"Wiederstein","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Yakubu, A., De Donato, M., and Imumorin, I.G. (2017). Modelling functional and structural impact of non-synonymous single nucleotide polymorphisms of the DQA1 gene of three Nigerian goat breeds. S. Afr. J. Anim. Sci., 47.","DOI":"10.4314\/sajas.v47i2.6"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Cristobal, S., Zemla, A., Fischer, D., Rychlewski, L., and Elofsson, A. (2001). A study of quality measures for protein threading models. BMC Bioinform., 2.","DOI":"10.1186\/1471-2105-2-5"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1110\/ps.0236803","article-title":"Can correct protein models be identified?","volume":"12","author":"Wallner","year":"2003","journal-title":"Protein Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1107\/S0021889892009944","article-title":"PROCHECK: A program to check the stereochemical quality of protein structures","volume":"26","author":"Laskowski","year":"1993","journal-title":"J. Appl. Crystallogr."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2174\/157340911795677602","article-title":"Molecular docking: A powerful approach for structure-based drug discovery","volume":"7","author":"Meng","year":"2011","journal-title":"Curr. Comput. Aided. Drug Des."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Patil, R., Das, S., Stanley, A., Yadav, L., Sudhakar, A., and Varma, A.K. (2010). Optimized Hydrophobic Interactions and Hydrogen Bonding at the Target-Ligand Interface Leads the Pathways of Drug-Designing. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012029"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1080\/07391102.2016.1277163","article-title":"Molecular modeling and statistical analysis in the design of derivatives of human dipeptidyl peptidase IV","volume":"36","author":"Pereira","year":"2018","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jmgm.2010.05.005","article-title":"LigAlign: Flexible ligand-based active site alignment and analysis","volume":"29","author":"Heifets","year":"2010","journal-title":"J. Mol. Graph. Model."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.3390\/molecules19021672","article-title":"Docking studies in target proteins involved in antibacterial action mechanisms: Extending the knowledge on standard antibiotics to antimicrobial mushroom compounds","volume":"19","author":"Alves","year":"2014","journal-title":"Molecules"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1021\/jm049092j","article-title":"Virtual screening workflow development guided by the \u201creceiver operating characteristic\u201d curve approach. Application to high-throughput docking on metabotropic glutamate receptor subtype 4","volume":"48","author":"Triballeau","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_62","first-page":"1","article-title":"Correlation between Virtual Screening Performance and Binding Site Descriptors of Protein Targets","volume":"2018","author":"Shamsara","year":"2018","journal-title":"Int. J. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"213","DOI":"10.32614\/RJ-2016-042","article-title":"EasyROC: An interactive web-tool for ROC curve analysis using R language environment","volume":"8","author":"Goksuluk","year":"2016","journal-title":"R J."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Cruz, J.V., Neto, M.F.A., Silva, L.B., da Ramos, R., da Costa, J., Brasil, D.S.B., Lobato, C.C., da Costa, G.V., Bittencourt, J.A.H.M., and da Silva, C.H.T.P. (2018). Identification of Novel Protein Kinase Receptor Type 2 Inhibitors Using Pharmacophore and Structure-Based Virtual Screening. Molecules, 23.","DOI":"10.3390\/molecules23020453"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1097\/JTO.0b013e3181ec173d","article-title":"Receiver operating characteristic curve in diagnostic test assessment","volume":"5","author":"Mandrekar","year":"2010","journal-title":"J. Thorac. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1002\/jmri.21947","article-title":"Relationship of temporal resolution to diagnostic performance for dynamic contrast enhanced MRI of the breast","volume":"30","author":"Macura","year":"2009","journal-title":"J. Magn. Reson. Imaging"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S1056-8719(00)00107-6","article-title":"Drug-like properties and the causes of poor solubility and poor permeability","volume":"44","author":"Lipinski","year":"2000","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 7.","DOI":"10.1038\/srep42717"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5149","DOI":"10.1016\/j.bmcl.2011.07.062","article-title":"Synthesis of various 3-nitropropionamides as Mycobacterium tuberculosis isocitrate lyase inhibitor","volume":"21","author":"Sriram","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"D1045","DOI":"10.1093\/nar\/gkv1072","article-title":"BindingDB in 2015: A public database for medicinal chemistry, computational chemistry and systems pharmacology","volume":"44","author":"Gilson","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1080\/14786410802250037","article-title":"Bioactive compounds from Lippia javanica and Hoslundia opposita","volume":"22","author":"Mujovo","year":"2008","journal-title":"Nat. Prod. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1093\/bioinformatics\/16.8.747","article-title":"PASS: Prediction of activity spectra for biologically active substances","volume":"16","author":"Lagunin","year":"2000","journal-title":"Bioinformatics"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.ijmyco.2016.06.020","article-title":"In silico PASS analysis and determination of antimycobacterial, antifungal, and antioxidant efficacies of maslinic acid in an extract rich in pentacyclic triterpenoids","volume":"5","author":"Jamkhande","year":"2016","journal-title":"Int. J. Mycobacteriol."},{"key":"ref_75","first-page":"1","article-title":"In-Vitro Susceptibility of Mycobacterium Ulcerans to Herbal Preparations","volume":"4","author":"Addo","year":"2007","journal-title":"Internet J. Trop. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e411","DOI":"10.1016\/j.ddtec.2013.02.003","article-title":"Induced fit docking, and the use of QM\/MM methods in docking","volume":"10","author":"Xu","year":"2013","journal-title":"Drug Discov. Today Technol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S1367-5931(02)00341-1","article-title":"Protein flexibility and drug design: How to hit a moving target","volume":"6","author":"Carlson","year":"2002","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3160","DOI":"10.1016\/j.bmc.2005.12.032","article-title":"New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies","volume":"14","author":"Farid","year":"2006","journal-title":"Bioorg. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1021\/jm050540c","article-title":"Novel procedure for modeling ligand\/receptor induced fit effects","volume":"49","author":"Sherman","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Kumar Deokar, H., Barch, H.P., and Buolamwini, J.K. (2017). Homology Modeling of Human Concentrative Nucleoside Transporters (hCNTs) and Validation by Virtual Screening and Experimental Testing to Identify Novel hCNT1 Inhibitors. Drug Des., 6.","DOI":"10.4172\/2169-0138.1000146"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.jmgm.2009.08.012","article-title":"Induced-fit docking studies of the active and inactive states of protein tyrosine kinases","volume":"28","author":"Zhong","year":"2009","journal-title":"J. Mol. Graph. Model."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.3390\/ijms15023253","article-title":"Rationalization of activity cliffs of a sulfonamide inhibitor of DNA methyltransferases with induced-fit docking","volume":"15","author":"Yoo","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_85","first-page":"1187","article-title":"Induced-fit docking and virtual screening for 8-hydroxy-3-methoxy- 5H-pyrido [2,1-c] pyrazin-5-one derivatives as inducible nitric oxide synthase inhibitors","volume":"6","author":"Luo","year":"2014","journal-title":"J. Chem. Pharm. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1747-0285.2005.00327.x","article-title":"Use of an Induced Fit Receptor Structure in Virtual Screening","volume":"67","author":"Sherman","year":"2006","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_87","unstructured":"(2018, June 13). How Is the IFD Score Calculated and What Is Its Units?. Available online: https:\/\/www.schrodinger.com\/kb\/307."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/0263-7855(90)80070-V","article-title":"WHAT IF: A molecular modeling and drug design program","volume":"8","author":"Vriend","year":"1990","journal-title":"J. Mol. Graph."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/bioinformatics\/bti770","article-title":"The SWISS-MODEL workspace: A web-based environment for protein structure homology modelling","volume":"22","author":"Arnold","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2714","DOI":"10.1002\/elps.1150181505","article-title":"SWISS-MODEL and the Swiss-Pdb Viewer: An environment for comparative protein modeling","volume":"18","author":"Guex","year":"1997","journal-title":"Electrophoresis"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1093\/nar\/gkg512","article-title":"CASTp: Computed Atlas of Surface Topography of proteins","volume":"31","author":"Binkowski","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"W116","DOI":"10.1093\/nar\/gkl282","article-title":"CASTp: Computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues","volume":"34","author":"Dundas","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1039\/C2CP42539D","article-title":"Unraveling the binding interaction and kinetics of a prospective anti-HIV drug with a model transport protein: Results and challenges","volume":"15","author":"Paul","year":"2013","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_94","first-page":"1636","article-title":"New PPAR\u03b1\/\u03b3\/\u03b4 Optimal Activator Rationally Designed by Computational Methods","volume":"27","author":"Padilha","year":"2016","journal-title":"J. Braz. Chem. Soc."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Khan, M.F., Nahar, N., Bin Rashid, R., Chowdhury, A., and Rashid, M.A. (2018). Computational investigations of physicochemical, pharmacokinetic, toxicological properties and molecular docking of betulinic acid, a constituent of Corypha taliera (Roxb.) with Phospholipase A2 (PLA2). BMC Complement. Altern. Med., 18.","DOI":"10.1186\/s12906-018-2116-x"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1021\/ci3001277","article-title":"ZINC: A free tool to discover chemistry for biology","volume":"52","author":"Irwin","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_97","first-page":"1","article-title":"Open Babel: An Open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1517\/17460441.2011.579100","article-title":"BindingDB and ChEMBL: Online compound databases for drug discovery","volume":"6","author":"Wassermann","year":"2011","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"576","DOI":"10.2174\/1381612823666170711112510","article-title":"Virtual Screening and Statistical Analysis in the Design of New Caffeine Analogues Molecules with Potential Epithelial Anticancer Activity","volume":"24","author":"Cruz","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Gey van Pittius, N.C., Sampson, S.L., Lee, H., Kim, Y., van Helden, P.D., and Warren, R.M. (2006). Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions. BMC Evol. Biol., 6.","DOI":"10.1186\/1471-2148-6-95"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"6582","DOI":"10.1021\/jm300687e","article-title":"Directory of useful decoys, enhanced (DUD-E): Better ligands and decoys for better benchmarking","volume":"55","author":"Mysinger","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the areas under two or more correlated receiver operating characteristic curves: A nonparametric approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/7\/1550\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:10:21Z","timestamp":1760195421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/7\/1550"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,27]]},"references-count":104,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2018,7]]}},"alternative-id":["molecules23071550"],"URL":"https:\/\/doi.org\/10.3390\/molecules23071550","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,27]]}}}