{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:03:28Z","timestamp":1792155808735,"version":"4.4.0"},"reference-count":86,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF)","award":["2021R1C1C1012076"],"award-info":[{"award-number":["2021R1C1C1012076"]}]},{"name":"National Research Foundation of Korea (NRF)","award":["2021R1A6A1A03044296"],"award-info":[{"award-number":["2021R1A6A1A03044296"]}]},{"name":"Ministry of Education","award":["2021R1C1C1012076"],"award-info":[{"award-number":["2021R1C1C1012076"]}]},{"name":"Ministry of Education","award":["2021R1A6A1A03044296"],"award-info":[{"award-number":["2021R1A6A1A03044296"]}]},{"name":"Chung-Ang University Research Scholarship Grants","award":["2021R1C1C1012076"],"award-info":[{"award-number":["2021R1C1C1012076"]}]},{"name":"Chung-Ang University Research Scholarship Grants","award":["2021R1A6A1A03044296"],"award-info":[{"award-number":["2021R1A6A1A03044296"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Natural product-derived drugs represent a cornerstone of modern pharmacotherapy, with many serving as essential therapeutic agents across diverse medical conditions. Recent advances in structural biology have provided unprecedented insights into the molecular mechanisms underlying their biological activities. This review presents a comprehensive structural analysis of five representative natural product-derived drugs: digoxin, simvastatin, morphine, paclitaxel, and penicillin. Through an examination of high-resolution crystal structures and cryo-electron microscopy (cryo-EM) data, we elucidate how these compounds interact with their respective protein targets and modulate biological functions. The structural data reveal diverse binding mechanisms\u2014ranging from competitive inhibition and covalent modification to allosteric modulation via conformational selection and induced fit\u2014demonstrating how natural products achieve their therapeutic effects through precise molecular recognition. These structural insights provide a molecular foundation for understanding natural product pharmacology and offer valuable guidance for structure-based drug design approaches in developing next-generation therapeutics.<\/jats:p>","DOI":"10.3390\/biom15091303","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T12:04:55Z","timestamp":1757505895000},"page":"1303","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Natural Product-Derived Drugs: Structural Insights into Their Biological Mechanisms"],"prefix":"10.3390","volume":"15","author":[{"given":"Yujeong","family":"Choi","sequence":"first","affiliation":[{"name":"College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Younghyun","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Joon","family":"Boo","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danbi","family":"Yoon","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7856-1236","authenticated-orcid":false,"given":"Jeong Seok","family":"Cha","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0864-2142","authenticated-orcid":false,"given":"Jiho","family":"Yoo","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural Products as Sources of New Drugs over the Nearly Four Decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1016\/j.biotechadv.2015.08.001","article-title":"Discovery and resupply of pharmacologically active plant-derived natural products: A review","volume":"33","author":"Atanasov","year":"2015","journal-title":"Biotechnol. Adv."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/nchem.2479","article-title":"Counting on natural products for drug design","volume":"8","author":"Rodrigues","year":"2016","journal-title":"Nat. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1080\/17460441.2025.2507382","article-title":"The latest advances with natural products in drug discovery and opportunities for the future: A 2025 update","volume":"20","author":"Xie","year":"2025","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nrd706","article-title":"High-throughput crystallography for lead discovery in drug design","volume":"1","author":"Blundell","year":"2002","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.chembiol.2003.09.002","article-title":"The process of structure-based drug design","volume":"10","author":"Anderson","year":"2003","journal-title":"Chem. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1161\/01.CIR.99.9.1265","article-title":"Digitalis","volume":"99","author":"Hauptman","year":"1999","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1146\/annurev-physiol-021909-135725","article-title":"The physiological significance of the cardiotonic steroid\/ouabain-binding site of the Na,K-ATPase","volume":"72","author":"Lingrel","year":"2010","journal-title":"Annu. Rev. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e2020438118","DOI":"10.1073\/pnas.2020438118","article-title":"Binding of cardiotonic steroids to Na(+),K(+)-ATPase in the E2P state","volume":"118","author":"Kanai","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hilbers, F., Kopec, W., Isaksen, T.J., Holm, T.H., Lykke-Hartmann, K., Nissen, P., Khandelia, H., and Poulsen, H. (2016). Tuning of the Na,K-ATPase by the beta subunit. Sci. Rep., 6.","DOI":"10.1038\/srep20442"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ren, Y., Wu, S., Burdette, J.E., Cheng, X., and Kinghorn, A.D. (2021). Structural Insights into the Interactions of Digoxin and Na(+)\/K(+)-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation. Molecules, 26.","DOI":"10.3390\/molecules26123672"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2123226119","DOI":"10.1073\/pnas.2123226119","article-title":"Cryoelectron microscopy of Na(+),K(+)-ATPase in the two E2P states with and without cardiotonic steroids","volume":"119","author":"Kanai","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1038\/nrd2682","article-title":"Novel therapeutic applications of cardiac glycosides","volume":"7","author":"Prassas","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1073\/pnas.1422997112","article-title":"Structures and characterization of digoxin- and bufalin-bound Na+,K+-ATPase compared with the ouabain-bound complex","volume":"112","author":"Laursen","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S0031-6997(25)00068-7","article-title":"The role of Na+,K+-ATPase in the inotropic action of digitalis","volume":"29","author":"Akera","year":"1977","journal-title":"Pharmacol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1113\/jphysiol.2006.111252","article-title":"The inotropic effect of cardioactive glycosides in ventricular myocytes requires Na+-Ca2+ exchanger function","volume":"575","author":"Altamirano","year":"2006","journal-title":"J. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"H919","DOI":"10.1152\/ajpheart.00131.2017","article-title":"How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na(+) pumps are crucial","volume":"313","author":"Blaustein","year":"2017","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrd1112","article-title":"Lovastatin and beyond: The history of the HMG-CoA reductase inhibitors","volume":"2","author":"Tobert","year":"2003","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/j.1472-8206.2004.00299.x","article-title":"Chemical, pharmacokinetic and pharmacodynamic properties of statins: An update","volume":"19","author":"Schachter","year":"2005","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1002\/jps.2600800905","article-title":"Relative lipophilicities, solubilities, and structure-pharmacological considerations of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors pravastatin, lovastatin, mevastatin, and simvastatin","volume":"80","author":"Serajuddin","year":"1991","journal-title":"J. Pharm. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1059344","article-title":"Structural mechanism for statin inhibition of HMG-CoA reductase","volume":"292","author":"Istvan","year":"2001","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1093\/emboj\/19.5.819","article-title":"Crystal structure of the catalytic portion of human HMG-CoA reductase: Insights into regulation of activity and catalysis","volume":"19","author":"Istvan","year":"2000","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gesto, D.S., Pereira, C.M.S., Cerqueira, N., and Sousa, S.F. (2020). An Atomic-Level Perspective of HMG-CoA-Reductase: The Target Enzyme to Treat Hypercholesterolemia. Molecules, 25.","DOI":"10.3390\/molecules25173891"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ancuceanu, R., Popovici, P.C., Draganescu, D., Busnatu, S., Lascu, B.E., and Dinu, M. (2024). QSAR Regression Models for Predicting HMG-CoA Reductase Inhibition. Pharmaceuticals, 17.","DOI":"10.3390\/ph17111448"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3957","DOI":"10.1073\/pnas.77.7.3957","article-title":"Mevinolin: A highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent","volume":"77","author":"Alberts","year":"1980","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1111\/j.1582-4934.2001.tb00172.x","article-title":"Statins: Mechanism of action and effects","volume":"5","author":"Stancu","year":"2001","journal-title":"J. Cell Mol. Med."},{"key":"ref_27","unstructured":"Sizar, O., Khare, S., Patel, P., and Talati, R. (2025). Statin Medications. StatPearls, StatPearls Publishing."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"D\u2019Imprima, E., and Kuhlbrandt, W. (2021). Current limitations to high-resolution structure determination by single-particle cryoEM. Q. Rev. Biophys., 54.","DOI":"10.1017\/S0033583521000020"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4361","DOI":"10.1016\/j.cell.2022.09.041","article-title":"Molecular recognition of morphine and fentanyl by the human mu-opioid receptor","volume":"185","author":"Zhuang","year":"2022","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nature14886","article-title":"Structural insights into micro-opioid receptor activation","volume":"524","author":"Huang","year":"2015","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10698","DOI":"10.1039\/D3CP05050E","article-title":"Exploring biased activation characteristics by molecular dynamics simulation and machine learning for the mu-opioid receptor","volume":"26","author":"Chen","year":"2024","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nature10954","article-title":"Crystal structure of the micro-opioid receptor bound to a morphinan antagonist","volume":"485","author":"Manglik","year":"2012","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cong, X., Campomanes, P., Kless, A., Schapitz, I., Wagener, M., Koch, T., and Carloni, P. (2015). Structural Determinants for the Binding of Morphinan Agonists to the mu-Opioid Receptor. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135998"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/s41586-018-0219-7","article-title":"Structure of the micro-opioid receptor-G(i) protein complex","volume":"558","author":"Koehl","year":"2018","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Lee, Y.S. (2022). Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery. Biomolecules, 12.","DOI":"10.3390\/biom12091241"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Abrimian, A., Kraft, T., and Pan, Y.X. (2021). Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073779"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1091\/mbc.e14-04-0916","article-title":"How Taxol\/paclitaxel kills cancer cells","volume":"25","author":"Weaver","year":"2014","journal-title":"Mol. Biol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e84791","DOI":"10.7554\/eLife.84791","article-title":"Structural insight into the stabilization of microtubules by taxanes","volume":"12","author":"Prota","year":"2023","journal-title":"eLife"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1002\/cmdc.200900044","article-title":"Recent advances in the study of the bioactive conformation of taxol","volume":"4","author":"Sun","year":"2009","journal-title":"ChemMedChem"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.jmb.2017.01.001","article-title":"Insights into the Distinct Mechanisms of Action of Taxane and Non-Taxane Microtubule Stabilizers from Cryo-EM Structures","volume":"429","author":"Kellogg","year":"2017","journal-title":"J. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3252","DOI":"10.1529\/biophysj.108.133884","article-title":"Taxol allosterically alters the dynamics of the tubulin dimer and increases the flexibility of microtubules","volume":"95","author":"Mitra","year":"2008","journal-title":"Biophys. J."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Steinmetz, M.O., and Prota, A.E. (2024). Structure-based discovery and rational design of microtubule-targeting agents. Curr. Opin. Struct. Biol., 87.","DOI":"10.1016\/j.sbi.2024.102845"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Bozdaganyan, M., Fedorov, V., Kholina, E., Kovalenko, I., Gudimchuk, N., and Orekhov, P. (2025). Exploring tubulin-paclitaxel binding modes through extensive molecular dynamics simulations. Sci. Rep., 15.","DOI":"10.1038\/s41598-025-92805-z"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5980","DOI":"10.1038\/s41467-023-41615-w","article-title":"Structural insights into the mechanism of GTP initiation of microtubule assembly","volume":"14","author":"Zhou","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1016\/j.jmb.2014.02.005","article-title":"The novel microtubule-destabilizing drug BAL27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization","volume":"426","author":"Prota","year":"2014","journal-title":"J. Mol. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/nature02393","article-title":"Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain","volume":"428","author":"Ravelli","year":"2004","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nature03566","article-title":"Structural basis for the regulation of tubulin by vinblastine","volume":"435","author":"Gigant","year":"2005","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1006\/jmbi.2001.5077","article-title":"Refined structure of alpha beta-tubulin at 3.5 A resolution","volume":"313","author":"Lowe","year":"2001","journal-title":"J. Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1021\/bi00062a003","article-title":"Assembly of purified GDP-tubulin into microtubules induced by taxol and taxotere: Reversibility, ligand stoichiometry, and competition","volume":"32","author":"Diaz","year":"1993","journal-title":"Biochemistry"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"R65","DOI":"10.1016\/S1074-5521(99)89002-4","article-title":"How Taxol stabilises microtubule structure","volume":"6","author":"Amos","year":"1999","journal-title":"Chem. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.tcb.2018.05.001","article-title":"Microtubule-Targeting Agents: Strategies To Hijack the Cytoskeleton","volume":"28","author":"Steinmetz","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1073\/pnas.54.4.1133","article-title":"Mechanism of action of penicillins: A proposal based on their structural similarity to acyl-D-alanyl-D-alanine","volume":"54","author":"Tipper","year":"1965","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1021\/cb400200h","article-title":"Binding of (5S)-penicilloic acid to penicillin binding protein 3","volume":"8","author":"Nettleship","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jmb.2010.10.024","article-title":"Crystal structures of penicillin-binding protein 3 from Pseudomonas aeruginosa: Comparison of native and antibiotic-bound forms","volume":"405","author":"Sainsbury","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1146\/annurev.mi.45.100191.000345","article-title":"Serine beta-lactamases and penicillin-binding proteins","volume":"45","author":"Ghuysen","year":"1991","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_56","first-page":"870","article-title":"Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus","volume":"9","author":"Lim","year":"2002","journal-title":"Nat. Struct. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"14345","DOI":"10.1021\/ja903773f","article-title":"Crystal structures of penicillin-binding protein 6 from Escherichia coli","volume":"131","author":"Chen","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4943","DOI":"10.1128\/AAC.00296-11","article-title":"Carbapenems: Past, present, and future","volume":"55","author":"Endimiani","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1128\/AAC.01009-09","article-title":"Updated functional classification of beta-lactamases","volume":"54","author":"Bush","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3110","DOI":"10.1021\/acschembio.2c00503","article-title":"Combined Structural Analysis and Molecular Dynamics Reveal Penicillin-Binding Protein Inhibition Mode with beta-Lactones","volume":"17","author":"Flanders","year":"2022","journal-title":"ACS Chem. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"10958","DOI":"10.1073\/pnas.1222308110","article-title":"Crystal structure of the high-affinity Na+K+-ATPase-ouabain complex with Mg2+ bound in the cation binding site","volume":"110","author":"Laursen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1038\/nature06419","article-title":"Crystal structure of the sodium-potassium pump","volume":"450","author":"Morth","year":"2007","journal-title":"Nature"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nature10361","article-title":"Crystal structure of the beta2 adrenergic receptor-Gs protein complex","volume":"477","author":"Rasmussen","year":"2011","journal-title":"Nature"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.cell.2014.03.053","article-title":"High-resolution microtubule structures reveal the structural transitions in alphabeta-tubulin upon GTP hydrolysis","volume":"157","author":"Alushin","year":"2014","journal-title":"Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.cbpa.2011.03.004","article-title":"Role of natural product diversity in chemical biology","volume":"15","author":"Hong","year":"2011","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Van Drie, J.H., and Tong, L. (2020). Cryo-EM as a powerful tool for drug discovery. Bioorg Med. Chem. Lett., 30.","DOI":"10.1016\/j.bmcl.2020.127524"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Murphy, C., Deplazes, E., Cranfield, C.G., and Garcia, A. (2020). The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228745"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1093\/jb\/mvae013","article-title":"GPCR signaling bias: An emerging framework for opioid drug development","volume":"175","author":"Kise","year":"2024","journal-title":"J. Biochem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.mib.2005.08.016","article-title":"Beta-lactam antibiotic resistance: A current structural perspective","volume":"8","author":"Wilke","year":"2005","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/nrd.2018.77","article-title":"Cryo-EM in drug discovery: Achievements, limitations and prospects","volume":"17","author":"Renaud","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"23889","DOI":"10.1021\/acsomega.5c00549","article-title":"AI-Driven Drug Discovery: A Comprehensive Review","volume":"10","author":"Ferreira","year":"2025","journal-title":"ACS Omega"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3814","DOI":"10.1021\/acs.chemrev.4c00567","article-title":"Synthetic Biology in Natural Product Biosynthesis","volume":"125","author":"Seshadri","year":"2025","journal-title":"Chem. Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1038\/s41592-023-01967-z","article-title":"Time-resolved cryo-EM using a combination of droplet microfluidics with on-demand jetting","volume":"20","author":"Torino","year":"2023","journal-title":"Nat. Methods"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6511","DOI":"10.1038\/s41467-023-42232-3","article-title":"An automated single-molecule FRET platform for high-content, multiwell plate screening of biomolecular conformations and dynamics","volume":"14","author":"Hartmann","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1038\/s41591-024-03486-6","article-title":"Digoxin for reduction of circulating tumor cell cluster size in metastatic breast cancer: A proof-of-concept trial","volume":"31","author":"Kurzeder","year":"2025","journal-title":"Nat. Med."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Zeng, W., Deng, H., Luo, Y., Zhong, S., Huang, M., and Tomlinson, B. (2024). Advances in statin adverse reactions and the potential mechanisms: A systematic review. J. Adv. Res., in press.","DOI":"10.1016\/j.jare.2024.12.020"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3799","DOI":"10.1111\/bph.17309","article-title":"Off-target effects of statins: Molecular mechanisms, side effects and the emerging role of kinases","volume":"181","author":"Liepinsh","year":"2024","journal-title":"Br. J. Pharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"8687","DOI":"10.1038\/s41467-024-52947-6","article-title":"Structural basis of mu-opioid receptor targeting by a nanobody antagonist","volume":"15","author":"Yu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1021\/acs.jpcb.4c05214","article-title":"Impact of Intracellular Proteins on mu-Opioid Receptor Structure and Ligand Binding","volume":"129","author":"Scott","year":"2025","journal-title":"J. Phys. Chem. B"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"960389","DOI":"10.3389\/fpain.2023.960389","article-title":"The opioid receptor: Emergence through millennia of pharmaceutical sciences","volume":"4","author":"Fairbanks","year":"2023","journal-title":"Front Pain Res"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Chew, Y.M., and Cross, R.A. (2023). Taxol acts differently on different tubulin isotypes. Commun. Biol., 6.","DOI":"10.1038\/s42003-023-05306-y"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4268","DOI":"10.1038\/s41467-023-39966-5","article-title":"Molecular basis of beta-lactam antibiotic resistance of ESKAPE bacterium E. faecium Penicillin Binding Protein PBP5","volume":"14","author":"Hunashal","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1007\/s40121-023-00771-8","article-title":"beta-Lactam Resistance in ESKAPE Pathogens Mediated Through Modifications in Penicillin-Binding Proteins: An Overview","volume":"12","author":"Sethuvel","year":"2023","journal-title":"Infect. Dis. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Lavollay, M., Buon, C., Le Moigne, V., Compain, F., Guyonvarch, A., and Fonvielle, M. (2024). Exploration of the role of the penicillin binding protein 2c (Pbp2c) in inducible beta-lactam resistance in Corynebacteriaceae. Front. Microbiol., 15.","DOI":"10.3389\/fmicb.2024.1327723"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/978-3-319-20164-1_13","article-title":"Druggability of Intrinsically Disordered Proteins","volume":"870","author":"Joshi","year":"2015","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/mSystems.00113-19","article-title":"Natural Products and Synthetic Biology: Where We Are and Where We Need to Go","volume":"4","author":"Kunakom","year":"2019","journal-title":"mSystems"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/9\/1303\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:43:13Z","timestamp":1760035393000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/9\/1303"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":86,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["biom15091303"],"URL":"https:\/\/doi.org\/10.3390\/biom15091303","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,10]]}}}