{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:12:56Z","timestamp":1791475976815,"version":"4.3.4"},"reference-count":75,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T00:00:00Z","timestamp":1697155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Saud University, Riyadh, Saudi Arabia","award":["RSPD2023R885"],"award-info":[{"award-number":["RSPD2023R885"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: Alstonia boonei, belonging to the family Apocynaceae, is one of the best-known medicinal plants in Africa and Asia. Stem back preparations are traditionally used as muscle relaxants. This study investigated the antispasmodic properties of Alstonia boonei Stem back and its constituents. Method: The freeze-dried aqueous Stem back extract of A. boonei, as well as dichloromethane (DCM), ethyl acetate, and aqueous fractions, were evaluated for their antispasmodic effect via the ex vivo method. Two compounds were isolated from the DCM fraction using chromatographic techniques, and their antispasmodic activity was evaluated. An in silico study was conducted by evaluating the interaction of isolated compounds with human PPARgamma-LBD and human carbonic anhydrase isozyme. Results: The Stem back crude extract, DCM, ethyl acetate, and aqueous fractions showed antispasmodic activity on high-potassium-induced (K+ 80 mM) contractions on isolated rat ileum with IC50 values of 0.03 \u00b1 0.20, 0.02 \u00b1 0.05, 0.03 \u00b1 0.14, and 0.90 \u00b1 0.06 mg\/mL, respectively. The isolated compounds from the DCM fraction were \u03b2-amyrin and boonein, with only boonein exhibiting antispasmodic activity on both high-potassium-induced (IC50 = 0.09 \u00b1 0.01 \u00b5g\/mL) and spontaneous (0.29 \u00b1 0.05 \u00b5g\/mL) contractions. However, \u03b2-amyrin had a stronger interaction with the two proteins during the simulation. Conclusion: The isolated compounds boonein and \u03b2-amyrin could serve as starting materials for the development of antispasmodic drugs.<\/jats:p>","DOI":"10.3390\/molecules28207069","type":"journal-article","created":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T10:16:12Z","timestamp":1697192172000},"page":"7069","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Antispasmodic Effect of Alstonia boonei De Wild. and Its Constituents: Ex Vivo and In Silico Approaches"],"prefix":"10.3390","volume":"28","author":[{"given":"Opeyemi Josephine","family":"Akinmurele","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Madonna University, Elele 512101, Nigeria"},{"name":"Department of Pharmacognosy, Faculty of Pharmacy, University of Ibadan, Ibadan 200005, Nigeria"},{"name":"Comsat International Institute of Technology (CIIT), Abbotabad 22020, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mubo Adeola","family":"Sonibare","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, University of Ibadan, Ibadan 200005, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony A.","family":"Elujoba","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife 220101, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1649-846X","authenticated-orcid":false,"given":"Akingbolabo Daniel","family":"Ogunlakin","sequence":"additional","affiliation":[{"name":"Phytomedicine, Molecular Toxicology, and Computational Biochemistry Research Laboratory (PMTCB-RL), Department of Biochemistry, Bowen University, Iwo 232101, Nigeria"},{"name":"H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oloruntoba Emmanuel","family":"Yeye","sequence":"additional","affiliation":[{"name":"H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"},{"name":"Department of Chemistry, Faculty of Science, University of Ibadan, Ibadan 200005, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1945-1739","authenticated-orcid":false,"given":"Gideon Ampoma","family":"Gyebi","sequence":"additional","affiliation":[{"name":"Natural products and Structural (Bio-Chem)-Informatics Research Laboratory (NpsBC-RI), Department of Biochemistry, Bingham University, Karu 961105, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9331-396X","authenticated-orcid":false,"given":"Oluwafemi Adeleke","family":"Ojo","sequence":"additional","affiliation":[{"name":"Phytomedicine, Molecular Toxicology, and Computational Biochemistry Research Laboratory (PMTCB-RL), Department of Biochemistry, Bowen University, Iwo 232101, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2565-6573","authenticated-orcid":false,"given":"Abdullah R.","family":"Alanzi","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 12271, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,13]]},"reference":[{"key":"ref_1","unstructured":"Osim, E.E. (2002). Elements of Gastrointestinal Tract Physiology, Helimo Associates Publishers."},{"key":"ref_2","unstructured":"Jackquelyn, C. (2022, December 12). Anticholinergics. Health Line Reference Library Publication. Available online: www.healthline.com."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1177\/2050640614558476","article-title":"Chronic constipation and co-morbidities: A prospective population-based nested case-control study","volume":"4","author":"Choung","year":"2016","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3923\/jpt.2019.1.8","article-title":"Antispasmodic and antidiarrhoeal activity of Newbouldia laevis, Cola nitida and Acanthus montanus leaf extracts on gastrointestinal smooth muscle","volume":"14","author":"Ibeh","year":"2018","journal-title":"J. Pharmacol. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2917","DOI":"10.1080\/13880209.2016.1194438","article-title":"Gut modulatory and butyrylcholinesterase inhibitory activities of Gaultheria trichophylla","volume":"54","author":"Alam","year":"2016","journal-title":"Pharm. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.jep.2009.09.010","article-title":"Antispasmodic and bronchodilator activities of Artemisia vulgaris are mediated through dual blockade of muscarinic receptors and calcium influx","volume":"126","author":"Khana","year":"2009","journal-title":"J. Ethnopharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"278","DOI":"10.3389\/fendo.2019.00278","article-title":"Regulation of gastrointestinal motility by motilin and ghrelin in vertebrates","volume":"10","author":"Kitazawa","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12944-016-0404-3","article-title":"Probing the intermolecular interactions of PPAR\u03b3-LBD with polyunsaturated fatty acids and their anti-inflammatory metabolites to infer most potential binding moieties","volume":"16","author":"Muralikumar","year":"2017","journal-title":"Lipids Health Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"154338","DOI":"10.1016\/j.metabol.2020.154338","article-title":"The role of peroxisome proliferator-activated receptors (PPAR) in immune responses","volume":"114","author":"Christofides","year":"2021","journal-title":"Metabolism"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lagan\u00e0, A.S., Vitale, S.G., Nigro, A., Sofo, V., Salmeri, F.M., Rossetti, P., Rapisarda, A.M.C., La Vignera, S., Condorelli, R.A., and Rizzo, G. (2016). Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs) in Dysregulated Metabolic Homeostasis, Inflammation and Cancer: Current Evidence and Future Perspectives. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17070999"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1007\/s00424-020-02417-x","article-title":"Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease","volume":"472","author":"Chadt","year":"2020","journal-title":"Pflug. Arch. Eur. J. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"730","DOI":"10.3389\/fphar.2020.00730","article-title":"Peroxisome Proliferator-Activated Receptors: Experimental Targeting for the Treatment of Inflammatory Bowel Diseases","volume":"11","author":"Decara","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.semcancer.2019.05.001","article-title":"Risk of colorectal cancer in inflammatory bowel diseases","volume":"64","author":"Nadeem","year":"2020","journal-title":"Semin. Cancer Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2019\/2624941","article-title":"Nuclear Receptors in the Pathogenesis and Management of Inflammatory Bowel Disease","volume":"2019","author":"Ning","year":"2019","journal-title":"Mediat. Inflamm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.3389\/fimmu.2019.01070","article-title":"Nuclear receptors regulate intestinal inflammation in the context of IBD","volume":"10","author":"Klepsch","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"106025","DOI":"10.1016\/j.phrs.2021.106025","article-title":"Modulatory role of the endocannabinoidome in the pathophysiology of the gastrointestinal tract","volume":"175","author":"Lian","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1042\/BCJ20160115","article-title":"Structure and function of carbonic anhydrases","volume":"473","author":"Supuran","year":"2016","journal-title":"Biochem. J."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Angeli, A., Carta, F., and Supuran, C.T. (2020). Carbonic Anhydrases: Versatile and Useful Biocatalysts in Chemistry and Biochemistry. Catalysts, 10.","DOI":"10.3390\/catal10091008"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nocentini, A., Donald, W.A., and Supuran, C.T. (2019). Carbonic Anhydrases, Academic Press.","DOI":"10.1016\/B978-0-12-816476-1.00008-3"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bua, S., Haapanen, S., Kuuslahti, M., Parkkila, S., and Supuran, C.T. (2019). Activation Studies of the \u03b2-Carbonic Anhydrase from the Pathogenic Protozoan Entamoeba histolytica with Amino Acids and Amines. Metabolites, 9.","DOI":"10.3390\/metabo9020026"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117111","DOI":"10.1016\/j.bmc.2022.117111","article-title":"Exploration of 1, 2, 3-triazole linked benzenesulfonamide derivatives as isoform selective inhibitors of human carbonic anhydrase","volume":"77","author":"Kakakhan","year":"2023","journal-title":"Bioorg. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1113\/JP283579","article-title":"Mitochondrial carbonic anhydrase VA and VB: Prop-erties and roles in health and disease","volume":"601","author":"Aspatwar","year":"2023","journal-title":"J. Physiol."},{"key":"ref_23","first-page":"111831","article-title":"Lycopene corrects metabolic syndrome and liver injury induced by high fat diet in obese rats through antioxidant, anti-inflammatory, antifibrotic pathways","volume":"141","author":"Albrahim","year":"2021","journal-title":"BioMedicine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4434","DOI":"10.1021\/acs.jmedchem.2c01975","article-title":"Advances in Epilepsy: Mechanisms, Clinical Trials, and Drug Therapies","volume":"66","author":"Hu","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_25","unstructured":"Sanghavi, S.F., and Swenson, E.R. (2023). Seminars in Respiratory and Critical Care Medicine, Thieme Medical Publishers, Inc."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kaczmarczyk, O., D\u0105bek-Drobny, A., Pi\u0105tek-Guziewicz, A., Wo\u017aniakiewicz, M., Pa\u015bko, P., Dobrowolska-Iwanek, J., Wo\u017aniakiewicz, A., Targosz, A., Ptak-Belowska, A., and Szczyrk, U. (2022). The Importance of Nutritional Aspects in the Assessment of In-flammation and Intestinal Barrier in Patients with Inflammatory Bowel Disease. Nutrients, 14.","DOI":"10.3390\/nu14214622"},{"key":"ref_27","first-page":"2501","article-title":"Treatment of irritable bowel syndrome","volume":"72","author":"Hadley","year":"2005","journal-title":"Am. Fam. Physician"},{"key":"ref_28","first-page":"93","article-title":"The antidiarrhoeal activity and phytoconstituents of the methanol extracts of Tecurium oliverianum","volume":"16","author":"Bayad","year":"2016","journal-title":"Glob. Vet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S0367-326X(03)00109-6","article-title":"Relaxant effect of essential oil of Melissa officinalis and citral oil on rat ileum contractions","volume":"74","author":"Sadraei","year":"2003","journal-title":"Fitoterapia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"142","DOI":"10.3390\/60300142","article-title":"Muscarinic Receptor Agonists and Antagonists","volume":"6","author":"Broadley","year":"2001","journal-title":"Molecules"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1021\/ol0705301","article-title":"Unique Monoterpenoid Indole Alkaloids from Alstonia scholaris","volume":"9","author":"Cai","year":"2007","journal-title":"Org. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1021\/ol702682h","article-title":"ChemInform Abstract: A Cage-Monoterpene Indole Alkaloid from Alstonia scholaris","volume":"10","author":"Cai","year":"2008","journal-title":"Org. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.phytochem.2009.03.007","article-title":"Alstonic acids A and B, unusual 2,3-secofernane triterpenoids from Alstonia scholaris","volume":"70","author":"Wang","year":"2009","journal-title":"Phytochemistry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1002\/hlca.200590186","article-title":"Three New Indole Alkaloids from the Leaves of Alstonia scholaris","volume":"88","author":"Zhou","year":"2005","journal-title":"Helvetica Chim. Acta"},{"key":"ref_35","first-page":"055","article-title":"Ethnobotanical survey of antimalarial plants used in Ogun State, Southwest Nigeria","volume":"4","author":"Idowu","year":"2010","journal-title":"Afr. J. Pharm. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0378-8741(99)00200-7","article-title":"Studies on the anti-inflammatory, antipyretic and analgesic properties of Alstonia boonei Stem back","volume":"71","author":"Olajide","year":"2000","journal-title":"J. Ethnopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"987","DOI":"10.4314\/tjpr.v7i2.14683","article-title":"Formulation of the extract of the Stem back of Alstonia boonei as tablet dosage form","volume":"7","author":"Majekodunmi","year":"2008","journal-title":"Trop. J. Pharm. Res."},{"key":"ref_38","unstructured":"Orwa, C., Mutua, A., Kindt, R., Jamnadass, R., and Anthony, S. (2022, December 12). Agroforestree Database: A Tree Reference and Selection Guide Version 402009. Available online: http:\/\/www.worldagroforestry.org\/publication\/agroforestree-database-tree-reference-andselection-guide-version-40."},{"key":"ref_39","unstructured":"Science Technology and Policy Research Institute (STEPRI), and Centre for Scientific and Industrial Research (CSIR) (2015). Ghana Herbal Pharmacopoeia, CSIR-INSTI. [2nd ed.]."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1002\/1099-1573(200012)14:8<630::AID-PTR773>3.0.CO;2-5","article-title":"Inhibition of glutathione S-transferases (GSTs) from parasitic nematodes by extracts from traditional Nigerian medicinal plants","volume":"14","author":"Fakae","year":"2000","journal-title":"Phytother. Res."},{"key":"ref_41","first-page":"323","article-title":"Re-search on African medicinal plants\u2014IV: Boonein, A new C-9 terpenoid lactone from Alstonia boonei: A possible precursor in the indole alkaloid biogenesis","volume":"39","author":"Nicoletti","year":"1983","journal-title":"Tetrahedron"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.3109\/13880209.2014.898078","article-title":"Beta-amyrin and Al-pha-amyrin acetate isolated from the Stem back of Alstonia boonei display profound anti-inflammatory activity","volume":"52","author":"Okoye","year":"2014","journal-title":"Pharm. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.9734\/EJMP\/2018\/41075","article-title":"Antispasmodic and Myorelaxant Activity of Organic Fractions from Origanum majorana L. on Intestinal Smooth Muscle of Rodents","volume":"23","author":"Makrane","year":"2018","journal-title":"Eur. J. Med. Plants"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1002\/ptr.1980","article-title":"Studies on spasmogenic and spasmolytic activities of Calendula officinalis flowers","volume":"20","author":"Bashir","year":"2006","journal-title":"Phytother. Res."},{"key":"ref_45","first-page":"13","article-title":"Activity of the stem-bark extract of Alstonia boonei De-Wild. (Apocynaceae) on human complement and polymorphonuclear leukocytes","volume":"17","author":"Taiwo","year":"1998","journal-title":"J. Ethnopharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/0024-3205(88)90674-1","article-title":"Calcium release in smooth muscle","volume":"42","author":"Karaki","year":"1988","journal-title":"Life Sci."},{"key":"ref_47","first-page":"321","article-title":"Calcium antagonism and calcium entry blockade","volume":"38","author":"Godfraind","year":"1986","journal-title":"Pharmacol. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"121","DOI":"10.3109\/13880208409070663","article-title":"Studies on the pharmacology of echitamine, an alkaloid from the Stem back of Alstonia boonei L. (Apocynaceae)","volume":"22","author":"Ojewole","year":"1984","journal-title":"Int. J. Crude Drug Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1055\/s-2006-959606","article-title":"Antispasmodic activity of benzylisoquinoline alkaloids analogous to papaverine","volume":"59","author":"Martin","year":"1993","journal-title":"Planta Medica"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1055\/s-2006-959561","article-title":"In vitro antispasmodic activity of peracetylated penstemonoside, aucubin and catalpol","volume":"60","author":"Martin","year":"1994","journal-title":"Planta Medica"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1055\/s-2006-957576","article-title":"Antispasmodic and relaxant activity of chelidonine, protopine, coptisine, and chelidonium majus extracts on isolated Guinea-pig lleum","volume":"64","author":"Hiller","year":"1998","journal-title":"Planta Medica"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1002\/ptr.3154","article-title":"A new and weakly antispasmodic protoberberine alkaloid from Rhizoma Coptidis","volume":"24","author":"Zhao","year":"2010","journal-title":"Phytotherapy Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1055\/s-2006-961381","article-title":"Antispasmodic activity of \u03b2-damascenone and E-phytol isolated from Ipomoea pes-caprae","volume":"58","author":"Pongprayoon","year":"1992","journal-title":"Planta Medica"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1021\/jf048404o","article-title":"Antispasmodic Saponins from Bulbs of Red Onion, Allium cepa L. Var. Tropea","volume":"53","author":"Corea","year":"2005","journal-title":"J. Agric. Food Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.phymed.2006.05.006","article-title":"Antispasmodic activity of an extract from Plantago lanceolata L. and some isolated compounds","volume":"14","author":"Fleer","year":"2007","journal-title":"Phytomedicine"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Zoofishan, Z., K\u00fasz, N., Csorba, A., T\u00f3th, G., Hajagos-T\u00f3th, J., Kothencz, A., G\u00e1sp\u00e1r, R., and Hunyadi, A. (2019). Antispasmodic Activity of Prenylated Phenolic Compounds from the Root Bark of Morus nigra. Molecules, 24.","DOI":"10.3390\/molecules24132497"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/nsb0902-646","article-title":"Molecular dynamics simulations of biomolecules","volume":"9","author":"Karplus","year":"2002","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-1-62703-050-2_11","article-title":"Molecular dynamics","volume":"1","author":"Cheng","year":"2012","journal-title":"Comput. Toxicol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1073\/pnas.1718910115","article-title":"Structural flexibility and protein adaptation to temperature: Molecular dynamics analysis of malate dehydrogenases of marine molluscs","volume":"115","author":"Dong","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.csbj.2020.03.013","article-title":"Classification of VUS and unclassified variants in BRCA1 BRCT repeats by molecular dynamics simulation","volume":"18","author":"Sinha","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.sbi.2015.12.002","article-title":"Advances in free-energy-based simulations of protein folding and ligand binding","volume":"36","author":"Perez","year":"2016","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1002\/ptr.2064","article-title":"Phytochemical, pharmacological and ethnobotanical studies of Rhazya stricta Decne. Review article","volume":"4","author":"Gilani","year":"2007","journal-title":"Phytother. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/0306-3623(91)90331-Y","article-title":"Differential effects of various Ca2+ antagonists","volume":"22","author":"Farre","year":"1991","journal-title":"Gen. Pharmacol. Vasc. Syst."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and Auto-DockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3697","DOI":"10.1021\/acs.jcim.0c00305","article-title":"PyPLIF HIPPOS: A molecular interaction fingerprinting tool for docking results of AutoDock Vina and plants","volume":"60","author":"Istyastono","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"ref_67","unstructured":"Bekker, H., Berendsen, H.J.C., Dijkstra, E.J., Achterop, S., Vondrumen, R.V., Vanderspoel, D., Sijbers, A., Keegstra, H., and Renardus, M.K.R. (1993). 4th International Conference on Computational Physics (PC 92), June 1992, World Scientific Publishing."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1002\/jcc.20090","article-title":"A biomolecular force field based on the free enthalpy of hydration and solvation: The GROMOS force-field parameter sets 53A5 and 53A6","volume":"25","author":"Oostenbrink","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_69","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","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_70","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_71","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1021\/ct300418h","article-title":"MMPBSA. py: An efficient program for end-state free energy calculations","volume":"8","author":"Miller","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","article-title":"gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS","volume":"17","author":"Valiente","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1021\/acschemneuro.7b00490","article-title":"What contributes to serotonin\u2013norepinephrine reuptake inhibitors\u2019 dual-targeting mechanism? The key role of transmembrane domain 6 in human serotonin and norepinephrine transporters revealed by molecular dynamics simulation","volume":"9","author":"Xue","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1080\/17460441.2021.1942836","article-title":"What is the current value of MM\/PBSA and MM\/GBSA methods in drug discovery?","volume":"16","author":"Tuccinardi","year":"2021","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"W443","DOI":"10.1093\/nar\/gkv315","article-title":"PLIP: Fully automated protein\u2013ligand interaction profiler","volume":"43","author":"Salentin","year":"2015","journal-title":"Nucleic Acids Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/20\/7069\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:06:19Z","timestamp":1760130379000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/20\/7069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,13]]},"references-count":75,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["molecules28207069"],"URL":"https:\/\/doi.org\/10.3390\/molecules28207069","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,13]]}}}