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However, the efficacy of these drugs has diminished due to mutations in the kinase domain, notably the T315I mutation. Therefore, in this study, new purine derivatives were designed as Bcr-Abl inhibitors based on 3D-QSAR studies. Methods: A database of 58 purines that inhibit Bcr-Abl was used to construct 3D-QSAR models. Using chemical information from these models, a small group of new purines was designed, synthesized, and evaluated in Bcr-Abl. Viability assays were conducted on imatinib-sensitive CML cells (K562 and KCL22) and imatinib-resistant cells (KCL22-B8). In silico analyses were performed to confirm the results. Results: Seven purines were easily synthesized (7a\u2013g). Compounds 7a and 7c demonstrated the highest inhibition activity on Bcr-Abl (IC50 = 0.13 and 0.19 \u03bcM), surpassing the potency of imatinib (IC50 = 0.33 \u03bcM). 7c exhibited the highest potency, with GI50 = 0.30 \u03bcM on K562 cells and 1.54 \u03bcM on KCL22 cells. The GI50 values obtained for non-neoplastic HEK293T cells indicated that 7c was less toxic than imatinib. Interestingly, KCL22-B8 cells (expressing Bcr-AblT315I) showed greater sensitivity to 7e and 7f than to imatinib (GI50 = 13.80 and 15.43 vs. &gt;20 \u03bcM, respectively). In silico analyses, including docking and molecular dynamics studies of Bcr-AblT315I, were conducted to elucidate the enhanced potency of 7e and 7f. Thus, this study provides in silico models to identify novel inhibitors that target a kinase of significance in CML.<\/jats:p>","DOI":"10.3390\/ph18060925","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T09:57:48Z","timestamp":1750327068000},"page":"925","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["3D-QSAR Design of New Bcr-Abl Inhibitors Based on Purine Scaffold and Cytotoxicity Studies on CML Cell Lines Sensitive and Resistant to Imatinib"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4040-1306","authenticated-orcid":false,"given":"David","family":"Cabezas","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica, Facultad de Ciencias, Universidad de Valpara\u00edso, Valpara\u00edso 2360102, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8189-0022","authenticated-orcid":false,"given":"Thal\u00eda","family":"Delgado","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Santiago de Chile 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guisselle","family":"Sep\u00falveda","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Santiago de Chile 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3578-6386","authenticated-orcid":false,"given":"Petra","family":"Kr\u0148\u00e1vkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Palack\u00fd University, Slechtitelu 27, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Voj\u00e1\u010dkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Palack\u00fd University, Slechtitelu 27, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5838-2118","authenticated-orcid":false,"given":"Vladim\u00edr","family":"Kry\u0161tof","sequence":"additional","affiliation":[{"name":"Department of Experimental Biology, Palack\u00fd University, Slechtitelu 27, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miroslav","family":"Strnad","sequence":"additional","affiliation":[{"name":"Laboratory of Growth Regulators, Palack\u00fd University and Institute of Experimental Botany, The Czech Academy of Sciences, Slechtitelu 27, 77900 Olomouc, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5084-3630","authenticated-orcid":false,"given":"Nicol\u00e1s Ignacio","family":"Silva","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Santiago de Chile 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1688-968X","authenticated-orcid":false,"given":"Javier","family":"Echeverr\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias del Ambiente, Facultad de Qu\u00edmica y Biolog\u00eda, Universidad de Santiago de Chile, Santiago de Chile 9170022, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6038-8439","authenticated-orcid":false,"given":"Christian","family":"Espinosa-Bustos","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Santiago de Chile 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0792-7733","authenticated-orcid":false,"given":"Guido","family":"Mellado","sequence":"additional","affiliation":[{"name":"Departamento de Ingenier\u00eda Inform\u00e1tica, Facultad de Ingenier\u00eda, Universidad Cat\u00f3lica de Temuco, Temuco 4780000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Luo","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica, Facultad de Ciencias, Universidad de Valpara\u00edso, Valpara\u00edso 2360102, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2434-8461","authenticated-orcid":false,"given":"Jaime","family":"Mella","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica, Facultad de Ciencias, Universidad de Valpara\u00edso, Valpara\u00edso 2360102, Chile"},{"name":"Centro de Investigaci\u00f3n Desarrollo e Innovaci\u00f3n de Productos Bioactivos (CInBIO), Escuela de Qu\u00edmica y Farmacia, Facultad de Farmacia, Universidad de Valpara\u00edso, Valpara\u00edso 2360102, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7620-2459","authenticated-orcid":false,"given":"Cristian O.","family":"Salas","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Org\u00e1nica, Facultad de Qu\u00edmica y de Farmacia, Pontificia Universidad Cat\u00f3lica de Chile, Santiago de Chile 7820436, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1182\/blood-2016-03-643544","article-title":"The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia","volume":"127","author":"Arber","year":"2016","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Westerweel, P.E., Te Boekhorst, P.A.W., Levin, M.-D., and Cornelissen, J.J. (2019). New Approaches and Treatment Combinations for the Management of Chronic Myeloid Leukemia. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.00665"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Komorowski, L., Fidyt, K., Patkowska, E., and Firczuk, M. (2020). Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage-Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165776"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.leukres.2010.04.016","article-title":"BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review","volume":"34","author":"An","year":"2010","journal-title":"Leuk. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2147\/JBM.S29132","article-title":"Cumulative clinical experience from a decade of use: Imatinib as first-line treatment of chronic myeloid leukemia","volume":"3","author":"Baran","year":"2012","journal-title":"J. Blood Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1080\/17474086.2024.2440776","article-title":"Understanding and overcoming resistance to tyrosine kinase inhibitors (TKIs) in Chronic myeloid leukemia (CML)","volume":"18","author":"Scalzulli","year":"2025","journal-title":"Expert. Rev. Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Carofiglio, F., Trisciuzzi, D., Gambacorta, N., Leonetti, F., Stefanachi, A., and Nicolotti, O. (2020). Bcr-Abl Allosteric Inhibitors: Where We Are and Where We Are Going to. Molecules, 25.","DOI":"10.3390\/molecules25184210"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s13045-018-0624-2","article-title":"Past, present, and future of Bcr-Abl inhibitors: From chemical development to clinical efficacy","volume":"11","author":"Rossari","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Nascimento, M., Moura, S., Parra, L., Vasconcellos, V., Costa, G., Leite, D., Dias, M., Fernandes, T.V.A., Hoelz, L., and Pimentel, L. (2024). Ponatinib: A Review of the History of Medicinal Chemistry behind Its Development. Pharmaceuticals, 17.","DOI":"10.3390\/ph17101361"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9244","DOI":"10.1073\/pnas.0600001103","article-title":"Activity of dual SRC-ABL inhibitors highlights the role of BCR\/ABL kinase dynamics in drug resistance","volume":"103","author":"Azam","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Delgado, T., Vesel\u00e1, D., Dost\u00e1lov\u00e1, H., Kry\u0161tof, V., Voj\u00e1\u010dkov\u00e1, V., Jorda, R., Castro, A., Bertrand, J., Rivera, G., and Fa\u00fandez, M. (2024). New Inhibitors of Bcr-Abl Based on 2,6,9-Trisubstituted Purine Scaffold Elicit Cytotoxicity in Chronic Myeloid Leukemia-Derived Cell Lines Sensitive and Resistant to TKIs. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16050649"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bertrand, J., Dost\u00e1lov\u00e1, H., Kry\u0161tof, V., Jorda, R., Delgado, T., Castro-Alvarez, A., Mella, J., Cabezas, D., Fa\u00fandez, M., and Espinosa-Bustos, C. (2022). Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14061294"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bertrand, J., Dost\u00e1lov\u00e1, H., Krystof, V., Jorda, R., Castro, A., Mella, J., Espinosa-Bustos, C., Mar\u00eda Zarate, A., and Salas, C.O. (2020). New 2,6,9-trisubstituted purine derivatives as Bcr-Abl and Btk inhibitors and as promising agents against leukemia. Bioorg. Chem., 94.","DOI":"10.1016\/j.bioorg.2019.103361"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Gagic, Z., Ruzic, D., Djokovic, N., Djikic, T., and Nikolic, K. (2019). In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs. Front. Chem., 7.","DOI":"10.3389\/fchem.2019.00873"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1021\/cb300729y","article-title":"De Novo Design of Protein Kinase Inhibitors by in Silico Identification of Hinge Region-Binding Fragments","volume":"8","author":"Urich","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e38309","DOI":"10.1016\/j.heliyon.2024.e38309","article-title":"In silico design and ADMET evaluation of new inhibitors for PIM1 kinase using QSAR studies, molecular docking, and molecular dynamic simulation","volume":"10","author":"Golestanifar","year":"2024","journal-title":"Heliyon"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1080\/08927022.2023.2172192","article-title":"In Silico study and design of some new potent threonine tyrosine kinase inhibitors using molecular docking simulation","volume":"49","author":"Azimi","year":"2023","journal-title":"Mol. Simul."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"102239","DOI":"10.1016\/j.rechem.2025.102239","article-title":"Rational computational Design of new-Generation EGFR tyrosine kinase (EGFR-TK) inhibitors","volume":"15","author":"Gond","year":"2025","journal-title":"Results Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Martins, D.M., Fernandes, P.O., Vieira, L.A., Maltarollo, V.G., and Moraes, A.H. (2024). Structure-Guided Drug Design Targeting Abl Kinase: How Structure and Regulation Can Assist in Designing New Drugs. ChemBioChem, 25.","DOI":"10.1002\/cbic.202400296"},{"key":"ref_20","first-page":"1094","article-title":"Design, in silico Evaluation, and Determination of Antitumor Activity of Potential Inhibitors Against Protein Kinases: Application to BCR-ABL Tyrosine Kinase","volume":"89","author":"Koroleva","year":"2024","journal-title":"Biochemistry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/nm1003","article-title":"VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo","volume":"10","author":"Harrington","year":"2004","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kumar, V., Parate, S., Zeb, A., Singh, P., Lee, G., Jung, T.S., Lee, K.W., and Ha, M.W. (2022). 3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.909111"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1007\/s00044-016-1642-7","article-title":"3D-QSAR studies on disubstituted dibenzosuberone derivatives as p38\u03b1 MAP kinase inhibitors using CoMFA and COMSIA","volume":"25","author":"Balasubramanian","year":"2016","journal-title":"Med. Chem. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S1093-3263(01)00123-1","article-title":"Beware of q2!","volume":"20","author":"Golbraikh","year":"2002","journal-title":"J. Mol. Graph. Model."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/minf.201000061","article-title":"Best Practices for QSAR Model Development, Validation, and Exploitation","volume":"29","author":"Tropsha","year":"2010","journal-title":"Mol. Inform."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/qsar.200390007","article-title":"The Importance of Being Earnest: Validation is the Absolute Essential for Successful Application and Interpretation of QSPR Models","volume":"22","author":"Tropsha","year":"2003","journal-title":"QSAR Comb. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/qsar.200710043","article-title":"On Some Aspects of Variable Selection for Partial Least Squares Regression Models","volume":"27","author":"Roy","year":"2008","journal-title":"QSAR Comb. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"141228","DOI":"10.1016\/j.molstruc.2024.141228","article-title":"Synthesis, antitumoral activity, and in silico studies on Smoothened receptor of new 2,6,9-trisubstituted purine derivatives","volume":"1328","author":"Guerrero","year":"2025","journal-title":"J. Mol. Struct."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Espinosa-Bustos, C., Bertrand, J., Villegas-Menares, A., Guerrero, S., Di Marcotullio, L., Navacci, S., Schulte, G., Kozielewicz, P., Bloch, N., and Villela, V. (2024). New Smoothened ligands based on the purine scaffold as potential agents for treating pancreatic cancer. Bioorg. Chem., 151.","DOI":"10.1016\/j.bioorg.2024.107681"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/jhet.4368","article-title":"Convergent synthesis, drug target prediction, and docking studies of new 2,6,9-trisubstituted purine derivatives","volume":"59","author":"Villegas","year":"2022","journal-title":"J. Heterocycl. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.1021\/acs.jctc.7b01170","article-title":"Predicting the Conformational Variability of Abl Tyrosine Kinase using Molecular Dynamics Simulations and Markov State Models","volume":"14","author":"Meng","year":"2018","journal-title":"J. Chem. Theory Comput."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1182\/blood-2005-03-1036","article-title":"High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: Correlation with clonal cytogenetic evolution but not response to therapy","volume":"106","author":"Willis","year":"2005","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1038\/sj.bjc.6603170","article-title":"AMN107 (nilotinib): A novel and selective inhibitor of BCR-ABL","volume":"94","author":"Weisberg","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/nature14119","article-title":"Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation","volume":"519","author":"Pemovska","year":"2015","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1002\/jcc.20289","article-title":"Scalable molecular dynamics with NAMD","volume":"26","author":"Phillips","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Bai, Q., Tan, S., Xu, T., Liu, H., Huang, J., and Yao, X. (2020). MolAICal: A soft tool for 3D drug design of protein targets by artificial intelligence and classical algorithm. Brief. Bioinform., 22.","DOI":"10.1093\/bib\/bbaa161"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1021\/tx200211v","article-title":"Improving Drug Candidates by Design: A Focus on Physicochemical Properties as a Means of Improving Compound Disposition and Safety","volume":"24","author":"Meanwell","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular Properties That Influence the Oral Bioavailability of Drug Candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1093\/comjnl\/7.2.155","article-title":"An efficient method for finding the minimum of a function of several variables without calculating derivatives","volume":"7","author":"Powell","year":"1964","journal-title":"Comput. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4130","DOI":"10.1021\/jm00050a010","article-title":"Molecular Similarity Indices in a Comparative Analysis (CoMSIA) of Drug Molecules to Correlate and Predict Their Biological Activity","volume":"37","author":"Klebe","year":"1994","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1002\/jcc.540100804","article-title":"Validation of the general purpose tripos 5.2 force field","volume":"10","author":"Clark","year":"1989","journal-title":"J. Comput. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.chemolab.2015.04.013","article-title":"On a simple approach for determining applicability domain of QSAR models","volume":"145","author":"Roy","year":"2015","journal-title":"Chemom. Intell. Lab. Syst."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Curik, N., Polivkova, V., Burda, P., Koblihova, J., Laznicka, A., Kalina, T., Kanderova, V., Brezinova, J., Ransdorfova, S., and Karasova, D. (2021). Somatic Mutations in Oncogenes Are in Chronic Myeloid Leukemia Acquired De Novo via Deregulated Base-Excision Repair and Alternative Non-Homologous End Joining. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.744373"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/jcc.21367","article-title":"CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields","volume":"31","author":"Vanommeslaeghe","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","article-title":"Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes","volume":"23","author":"Ryckaert","year":"1977","journal-title":"J. Comput. Phys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1002\/jcc.23354","article-title":"CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data","volume":"34","author":"Huang","year":"2013","journal-title":"J. Comput. Chem."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/6\/925\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:54:56Z","timestamp":1760032496000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/6\/925"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,19]]},"references-count":48,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ph18060925"],"URL":"https:\/\/doi.org\/10.3390\/ph18060925","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,19]]}}}