{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:41:38Z","timestamp":1791859298943,"version":"4.3.4"},"reference-count":104,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria","award":["BG-RRP-2.004-0004-C01"],"award-info":[{"award-number":["BG-RRP-2.004-0004-C01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: Ferrocene-containing compounds have gained attention in medicinal chemistry due to their unique redox and structural properties. This study investigates ferrocene-based analogues of imatinib and nilotinib to define their binding determinants within the ABL1 kinase domain using an integrated in silico approach, in relation to their previously reported cytotoxic activity. Methods: Ligand geometries were optimized at the B3LYP\/def2-TZVP level with D3(BJ) dispersion and SMD solvation. Molecular docking against ABL1 (PDB ID: 2HYY) was performed using Glide SP, validated by re-docking and enrichment screening. Docked poses were refined using MM-GBSA (Prime, VSGB 2.1\/OPLS4). The most active compounds (9 and 15a), together with the inactive control 15e, were subjected to three independent 500 ns molecular dynamics simulations (Desmond, OPLS4), followed by trajectory analysis including RMSD, RMSF, radius of gyration, SASA, and polar surface area. Results: Compounds 9 and 15a maintained stable binding within the ATP-binding pocket despite lacking the canonical hinge interaction with Met318, indicating hinge-independent binding. Their binding was mainly driven by interactions with Asp381 (DFG motif) and cation\u2013\u03c0 contacts with Lys271. In contrast, the compound 15e showed unstable binding, increased conformational flexibility, reduced pocket burial, and loss of key stabilizing interactions. Active compounds also preserved stable P-loop dynamics, with Tyr253 engagement suggesting a role in loop stabilization. Compound 9 exhibited the most constrained and reproducible binding mode among all analogues. Conclusions: Ferrocene-based analogues can sustain stable ABL1 binding via non-classical interaction networks independent of hinge recognition. The clear distinction between active compounds and the inactive analogue 15e supports the robustness of the proposed binding mode and provides a structural basis for their reported cytotoxic activity. These findings support further experimental evaluation of ferrocene-containing scaffolds as potential BCR-ABL1 inhibitors.<\/jats:p>","DOI":"10.3390\/molecules31122156","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:18:43Z","timestamp":1781860723000},"page":"2156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Non-Classical Binding Mechanisms of Ferrocene-Modified Imatinib and Nilotinib Analogues in BCR-ABL1 Kinase Revealed by Computational Analysis"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3815-6043","authenticated-orcid":false,"given":"Rostislava","family":"Angelova","sequence":"first","affiliation":[{"name":"Chemistry Department, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria"},{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8893-0346","authenticated-orcid":false,"given":"Georgi","family":"Stavrakov","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria"},{"name":"Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. 9, 1113 Sofia, Bulgaria"},{"name":"Centre of Excellence in Informatics and Information and Communication Technologies, Bulgarian Academy of Sciences, Akad. Georgi Bonchev Str., Block 2 and 25A, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6680-877X","authenticated-orcid":false,"given":"Danislav S.","family":"Spassov","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria"},{"name":"Centre of Excellence in Informatics and Information and Communication Technologies, Bulgarian Academy of Sciences, Akad. Georgi Bonchev Str., Block 2 and 25A, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2841-7089","authenticated-orcid":false,"given":"Georgi","family":"Momekov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9761-0355","authenticated-orcid":false,"given":"Mariyana","family":"Atanasova","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav Str., 1000 Sofia, Bulgaria"},{"name":"Centre of Excellence in Informatics and Information and Communication Technologies, Bulgarian Academy of Sciences, Akad. Georgi Bonchev Str., Block 2 and 25A, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/S0002-9343(96)00061-7","article-title":"Chronic Myelogenous Leukemia: A Review","volume":"100","author":"Cortes","year":"1996","journal-title":"Am. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1056\/NEJM199907153410306","article-title":"The Biology of Chronic Myeloid Leukemia","volume":"341","author":"Faderl","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_3","first-page":"85","article-title":"Chromosome Studies on Normal and Leukemic Human Leukocytes","volume":"25","author":"Nowell","year":"1960","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_4","first-page":"1013","article-title":"Chromosome Studies in Human Leukemia. II. Chronic Granulocytic Leukemia","volume":"27","author":"Nowell","year":"1961","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/BF01630378","article-title":"The minute chromosome (Ph1) in chronic granulocytic leukemia","volume":"8","author":"Nowell","year":"1962","journal-title":"Blut"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4758","DOI":"10.1182\/blood.V92.12.4758","article-title":"Lineage Involvement of Stem Cells Bearing the Philadelphia Chromosome in Chronic Myeloid Leukemia in the Chronic Phase as Shown by a Combination of Fluorescence-Activated Cell Sorting and Fluorescence in Situ Hybridization","volume":"92","author":"Takahashi","year":"1998","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6151","DOI":"10.1093\/emboj\/16.20.6151","article-title":"Transformation of Hematopoietic Cells by BCR\/ABL Requires Activation of a PI-3k\/Akt-Dependent Pathway","volume":"16","author":"Skorski","year":"1997","journal-title":"EMBO J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1126\/science.278.5338.687","article-title":"Interleukin-3-Induced Phosphorylation of BAD through the Protein Kinase Akt","volume":"278","author":"Page","year":"1997","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1084\/jem.191.6.977","article-title":"Blockade of the Bcr-Abl Kinase Activity Induces Apoptosis of Chronic Myelogenous Leukemia Cells by Suppressing Signal Transducer and Activator of Transcription 5\u2013Dependent Expression of Bcl-XL","volume":"191","author":"Horita","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1006\/mcbr.2000.0231","article-title":"STAT5-Dependent CyclinD1 and Bcl-xL Expression in Bcr-Abl-Transformed Cells","volume":"3","author":"Raaijmakers","year":"2000","journal-title":"Mol. Cell Biol. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1182\/blood.V96.6.2269","article-title":"Bcr\/Abl Activates Transcription of theBcl-X Gene through STAT5","volume":"96","author":"Gesbert","year":"2000","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1182\/blood.V95.6.2118","article-title":"STAT5 Activation Contributes to Growth and Viability in Bcr\/Abl-Transformed Cells","volume":"95","author":"Sillaber","year":"2000","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1182\/blood.V96.2.664","article-title":"The Grb2 Binding Site Is Required for the Induction of Chronic Myeloid Leukemia-like Disease in Mice by the Bcr\/Abl Tyrosine Kinase","volume":"96","author":"Million","year":"2000","journal-title":"Blood"},{"key":"ref_14","unstructured":"Szeto, M. (2017). Mechanisms of RAS\/MAPK Signaling by BCR-ABL1 in Chronic Myeloid Leukemia, UCSF."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1056\/NEJMoa022457","article-title":"Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia","volume":"348","author":"Guilhot","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e694","DOI":"10.1002\/mco2.694","article-title":"Mechanisms of Resistance to Tyrosine Kinase Inhibitor-Targeted Therapy and Overcoming Strategies","volume":"5","author":"Ou","year":"2024","journal-title":"MedComm"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1038\/nsmb.1486","article-title":"Activation of Tyrosine Kinases by Mutation of the Gatekeeper Threonine","volume":"15","author":"Azam","year":"2008","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1182\/blood-2010-12-326405","article-title":"BCR-ABL Kinase Domain Mutation Analysis in Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors: Recommendations from an Expert Panel on Behalf of European LeukemiaNet","volume":"118","author":"Soverini","year":"2011","journal-title":"Blood"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5196","DOI":"10.1182\/blood-2019-131694","article-title":"The \u201cGatekeeper\u201d Mutation T315I in BCR\/ABL Confers Additional Oncogenic Activities to Philadelphia Chromosome Positive Leukemia","volume":"134","author":"Zafar","year":"2019","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.hoc.2017.04.007","article-title":"Mechanisms of Resistance to ABL Kinase Inhibition in Chronic Myeloid Leukemia and the Development of Next Generation ABL Kinase Inhibitors","volume":"31","author":"Patel","year":"2017","journal-title":"Hematol. Clin. N. Am."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Alves, R., Gon\u00e7alves, A.C., Rutella, S., Almeida, A.M., De Las Rivas, J., Trougakos, I.P., and Sarmento Ribeiro, A.B. (2021). Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia\u2014From Molecular Mechanisms to Clinical Relevance. Cancers, 13.","DOI":"10.3390\/cancers13194820"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5931","DOI":"10.1021\/cr0101510","article-title":"Bioorganometallic Chemistry of Ferrocene","volume":"104","year":"2004","journal-title":"Chem. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"0066","DOI":"10.1038\/s41570-017-0066","article-title":"The Medicinal Chemistry of Ferrocene and Its Derivatives","volume":"1","author":"Patra","year":"2017","journal-title":"Nat. Rev. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"C23","DOI":"10.1016\/S0022-328X(00)80708-1","article-title":"Organometallic Derivatives of Penicillins and Cephalosporins a New Class of Semi-Synthetic Antibiotics","volume":"85","author":"Edwards","year":"1975","journal-title":"J. Organomet. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"C49","DOI":"10.1016\/S0022-328X(00)82406-7","article-title":"1,1\u2032-Ferrocenyldiacetic Acid Anhydride and Its Use in the Preparation of Heteroannularly Substituted Ferrocenyl-Penicillins and -Cephalosporins","volume":"122","author":"Edwards","year":"1976","journal-title":"J. Organomet. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/1681039b0","article-title":"A New Type of Organo-Iron Compound","volume":"168","author":"Kealy","year":"1951","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Miller, S.A., Tebboth, J.A., and Tremaine, J.F. (1952). Dicyclopentadienyliron. J. Chem. Soc., 632\u2013635.","DOI":"10.1039\/jr9520000632"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1515\/znb-1952-0701","article-title":"Cyclopentadien-Metallkomplexe, Ein Neuer Typ Metallorganischer Verbindungen","volume":"7","author":"Fischer","year":"1952","journal-title":"Z. F\u00fcr Naturforschung B"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1021\/ja01128a527","article-title":"The Structure of Iron Bis-Cyclopentadienyl","volume":"74","author":"Wilkinson","year":"1952","journal-title":"J. Am. Chem. Soc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/0041-008X(69)90067-2","article-title":"Chronic Toxicity of Dicyclopentadienyliron (Ferrocene) in Dogs","volume":"15","author":"Yeary","year":"1969","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1021\/jm00202a016","article-title":"Ferrocenyl Polyamines as Agents for the Chemoimmunotherapy of Cancer","volume":"21","author":"Fiorina","year":"1978","journal-title":"J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3715","DOI":"10.1021\/jm970401y","article-title":"Synthesis and Antimalarial Activity In Vitro and In Vivo of a New Ferrocene\u2212Chloroquine Analogue","volume":"40","author":"Biot","year":"1997","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15896","DOI":"10.1038\/s41598-017-16154-2","article-title":"Ferroquine, the next Generation Antimalarial Drug, Has Antitumor Activity","volume":"7","author":"Kondratskyi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1186\/s12936-021-03749-4","article-title":"A Randomized, Double-Blind, Phase 2b Study to Investigate the Efficacy, Safety, Tolerability and Pharmacokinetics of a Single-Dose Regimen of Ferroquine with Artefenomel in Adults and Children with Uncomplicated Plasmodium Falciparum Malaria","volume":"20","author":"Adoke","year":"2021","journal-title":"Malar. J."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Snegur, L.V. (2022). Modern Trends in Bio-Organometallic Ferrocene Chemistry. Inorganics, 10.","DOI":"10.3390\/inorganics10120226"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1021\/ar50143a006","article-title":"Molecular Structure and Bonding in the 3d Metallocenes","volume":"12","author":"Haaland","year":"1979","journal-title":"Acc. Chem. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1107\/S0567740879005604","article-title":"A Neutron Diffraction Study of the Crystal Structure of Ferrocene","volume":"35","author":"Takusagawa","year":"1979","journal-title":"Acta Crystallogr. B Struct. Crystallogr. Cryst. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S0022-328X(00)82382-7","article-title":"On the Molecular Structure of Ferrocene, Fe(C5H5)2","volume":"5","author":"Bohn","year":"1966","journal-title":"J. Organomet. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13850","DOI":"10.1021\/jp062896l","article-title":"An All-Atom Force Field for Metallocenes","volume":"110","author":"Lopes","year":"2006","journal-title":"J. Phys. Chem. A"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15665","DOI":"10.1002\/anie.202004239","article-title":"Robust Atomistic Modeling of Materials, Organometallic, and Biochemical Systems","volume":"59","author":"Spicher","year":"2020","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and Testing of a General Amber Force Field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"114502","DOI":"10.1063\/5.0019056","article-title":"A Fast and High-Quality Charge Model for the next Generation General AMBER Force Field","volume":"153","author":"He","year":"2020","journal-title":"J. Chem. Phys."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1021\/acs.jcim.5b00674","article-title":"MCPB.Py: A Python Based Metal Center Parameter Builder","volume":"56","author":"Li","year":"2016","journal-title":"J. Chem. Inf. Model."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7827","DOI":"10.1021\/acs.jctc.1c00832","article-title":"A Universal Force Field for Materials, Periodic GFN-FF: Implementation and Examination","volume":"17","author":"Gale","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","article-title":"OPLS4: Improving Force Field Accuracy on Challenging Regimes of Chemical Space","volume":"17","author":"Lu","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1039\/D3MD00030C","article-title":"Ferrocene Modified Analogues of Imatinib and Nilotinib as Potent Anti-Cancer Agents","volume":"14","author":"Philipova","year":"2023","journal-title":"RSC Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1177\/1947601912462126","article-title":"The Ins and Outs of Bcr-Abl Inhibition","volume":"3","author":"Reddy","year":"2012","journal-title":"Genes. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1073\/pnas.0811223106","article-title":"A Conserved Protonation-Dependent Switch Controls Drug Binding in the Abl Kinase","volume":"106","author":"Shan","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/cncr.26225","article-title":"The Rise and Fall of Gatekeeper Mutations? The BCR-ABL1 T315I Paradigm","volume":"118","author":"Gibbons","year":"2012","journal-title":"Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1107\/S0907444906047287","article-title":"Structural Biology Contributions to the Discovery of Drugs to Treat Chronic Myelogenous Leukaemia","volume":"63","author":"Fendrich","year":"2007","journal-title":"Acta Cryst. D"},{"key":"ref_51","unstructured":"Strzelczyk, P., Pla\u017cuk, D., and Bujacz, G. (2026, June 15). Crystal Structure of Avidin in Complex with Ferrocene Homobiotin Derivative: PDB ID: 5MYQ, RCSB Protein Data Bank. Available online: https:\/\/www.rcsb.org\/structure\/5MYQ."},{"key":"ref_52","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_53","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1093\/bioinformatics\/btab080","article-title":"Generating Property-Matched Decoy Molecules Using Deep Learning","volume":"37","author":"Imrie","year":"2021","journal-title":"Bioinformatics"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4778","DOI":"10.1182\/blood.V108.11.4778.4778","article-title":"Synergistic Activity of Nilotinib and Established Chemotherapeutic Agents in Imatinib-Sensitive and -Resistant BCR-ABL-Positive Leukemia Cells","volume":"108","author":"Radujkovic","year":"2006","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Spassov, D.S., Atanasova, M., and Doytchinova, I. (2023). Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411610"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Spassov, D.S. (2024). Binding Affinity Determination in Drug Design: Insights from Lock and Key, Induced Fit, Conformational Selection, and Inhibitor Trapping Models. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25137124"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Spassov, D.S., Atanasova, M., and Doytchinova, I. (2024). Inhibitor Trapping in Kinases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063249"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"104694","DOI":"10.1016\/j.drudis.2026.104694","article-title":"Ligand Trapping as a Key Mechanism Governing Drug Residence Time, Binding Affinity, and Potency","volume":"31","author":"Spassov","year":"2026","journal-title":"Drug Discov. Today"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"379-IN4","DOI":"10.1016\/0022-2836(71)90324-X","article-title":"The Interpretation of Protein Structures: Estimation of Static Accessibility","volume":"55","author":"Lee","year":"1971","journal-title":"J. Mol. Biol."},{"key":"ref_60","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_61","first-page":"4236","article-title":"Crystal Structures of the Kinase Domain of C-Abl in Complex with the Small Molecule Inhibitors PD173955 and Imatinib (STI-571)1","volume":"62","author":"Nagar","year":"2002","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1021\/cb500129t","article-title":"Exploration of Type II Binding Mode: A Privileged Approach for Kinase Inhibitor Focused Drug Discovery?","volume":"9","author":"Zhao","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1002\/pro.5560071127","article-title":"Cation-\u03c0 (Na+-Trp) Interactions in the Crystal Structure of Tetragonal Lysozyme","volume":"7","author":"Wouters","year":"1998","journal-title":"Protein Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"9459","DOI":"10.1073\/pnas.96.17.9459","article-title":"Cation-\u03c0 Interactions in Structural Biology","volume":"96","author":"Gallivan","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"124","DOI":"10.32607\/20758251-2009-1-1-124-127","article-title":"The Role of Stacking Interactions in Complexes of Proteins with Adenine and Guanine Fragments of Ligands","volume":"1","author":"Pyrkov","year":"2009","journal-title":"Acta Naturae"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/cbdd.13084","article-title":"Aromatic Interactions at the Ligand-Protein Interface: Implications for the Development of Docking Scoring Functions","volume":"91","author":"Brylinski","year":"2018","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Ivanov, S.M. (2026). An Efficient Computational Chemistry Approach to Generating Negative Data for Drug Discovery Pipeline Validation. Front. Bioinform., 6.","DOI":"10.3389\/fbinf.2026.1756279"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.ccr.2011.03.003","article-title":"Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036","volume":"19","author":"Chan","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Levinson, N.M., Kuchment, O., Shen, K., Young, M.A., Koldobskiy, M., Karplus, M., Cole, P.A., and Kuriyan, J. (2006). A Src-Like Inactive Conformation in the Abl Tyrosine Kinase Domain. PLoS Biol., 4.","DOI":"10.2210\/pdb2g2h\/pdb"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e70005","DOI":"10.1002\/ardp.70005","article-title":"Structure and Dynamics of the ABL1 Tyrosine Kinase and Its Important Role in Chronic Myeloid Leukemia","volume":"358","author":"Irgit","year":"2025","journal-title":"Arch. Der Pharm."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"10700","DOI":"10.1073\/pnas.162140299","article-title":"Clinical Resistance to the Kinase Inhibitor STI-571 in Chronic Myeloid Leukemia by Mutation of Tyr-253 in the Abl Kinase Domain P-Loop","volume":"99","author":"Roumiantsev","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/sj.leu.2404151","article-title":"The Bcr-Abl Mutations T315I and Y253H Do Not Confer a Growth Advantage in the Absence of Imatinib","volume":"20","author":"Miething","year":"2006","journal-title":"Leukemia"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1758-2946-4-17","article-title":"Avogadro: An Advanced Semantic Chemical Editor, Visualization, and Analysis Platform","volume":"4","author":"Hanwell","year":"2012","journal-title":"J. Cheminform"},{"key":"ref_74","unstructured":"Team, T.A. (2026, March 02). Avogadro\u2014Free Cross-Platform Molecular Editor. Available online: https:\/\/avogadro.cc\/."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e70019","DOI":"10.1002\/wcms.70019","article-title":"Software Update: The ORCA Program System\u2014Version 6.0","volume":"15","author":"Neese","year":"2025","journal-title":"WIREs Comput. Mol. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1103\/PhysRevB.37.785","article-title":"Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density","volume":"37","author":"Lee","year":"1988","journal-title":"Phys. Rev. B"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1063\/1.464913","article-title":"Density-functional Thermochemistry. III. The Role of Exact Exchange","volume":"98","author":"Becke","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1002\/jcc.10318","article-title":"An Improvement of the Resolution of the Identity Approximation for the Formation of the Coulomb Matrix","volume":"24","author":"Neese","year":"2003","journal-title":"J. Comput. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1039\/b508541a","article-title":"Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: Design and Assessment of Accuracy","volume":"7","author":"Weigend","year":"2005","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.chemphys.2008.10.036","article-title":"Efficient, Approximate and Parallel Hartree\u2013Fock and Hybrid DFT Calculations. A \u2018Chain-of-Spheres\u2019 Algorithm for the Hartree\u2013Fock Exchange","volume":"356","author":"Neese","year":"2009","journal-title":"Chem. Phys."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"154104","DOI":"10.1063\/1.3382344","article-title":"A Consistent and Accurate Ab. Initio Parametrization of Density Functional Dispersion Correction (DFT-D) for the 94 Elements H-Pu","volume":"132","author":"Grimme","year":"2010","journal-title":"J. Chem. Phys."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1002\/jcc.21759","article-title":"Effect of the Damping Function in Dispersion Corrected Density Functional Theory","volume":"32","author":"Grimme","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"6378","DOI":"10.1021\/jp810292n","article-title":"Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions","volume":"113","author":"Marenich","year":"2009","journal-title":"J. Phys. Chem. B"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0022-2836(02)00470-9","article-title":"On the Role of the Crystal Environment in Determining Protein Side-Chain Conformations","volume":"320","author":"Jacobson","year":"2002","journal-title":"J. Mol. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/prot.10613","article-title":"A Hierarchical Approach to All-Atom Protein Loop Prediction","volume":"55","author":"Jacobson","year":"2004","journal-title":"Proteins"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and Ligand Preparation: Parameters, Protocols, and Influence on Virtual Screening Enrichments","volume":"27","author":"Adzhigirey","year":"2013","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide:\u2009 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_88","doi-asserted-by":"crossref","first-page":"7106","DOI":"10.1021\/acs.jctc.1c00810","article-title":"Efficient Exploration of Chemical Space with Docking and Deep Learning","volume":"17","author":"Yang","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1021\/acs.jctc.3c00044","article-title":"Epik: pKa and Protonation State Prediction through Machine Learning","volume":"19","author":"Johnston","year":"2023","journal-title":"J. Chem. Theory Comput."},{"key":"ref_90","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. Cheminformatics"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"D945","DOI":"10.1093\/nar\/gkw1074","article-title":"The ChEMBL Database in 2017","volume":"45","author":"Gaulton","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1021\/jm030644s","article-title":"Glide:\u2009 A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening","volume":"47","author":"Halgren","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jmgm.2010.05.008","article-title":"Analysis and Comparison of 2D Fingerprints: Insights into Database Screening Performance Using Eight Fingerprint Methods","volume":"29","author":"Duan","year":"2010","journal-title":"J. Mol. Graph. Model."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA Methods to Estimate Ligand-Binding Affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"10983","DOI":"10.1021\/jp982533o","article-title":"Generalized Born Model Based on a Surface Integral Formulation","volume":"102","author":"Ghosh","year":"1998","journal-title":"J. Phys. Chem. B"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Bowers, K.J., Chow, D.E., Xu, H., Dror, R.O., Eastwood, M.P., Gregersen, B.A., Klepeis, J.L., Kolossvary, I., Moraes, M.A., and Sacerdoti, F.D. (2006, January 11\u201317). Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters. Proceedings of the 2006 ACM\/IEEE Conference on Supercomputing, SC\u201906 2006, Tampa, FL, USA.","DOI":"10.1145\/1188455.1188544"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of Simple Potential Functions for Simulating Liquid Water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1063\/1.447334","article-title":"A Unified Formulation of the Constant Temperature Molecular Dynamics Methods","volume":"81","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1103\/PhysRevA.31.1695","article-title":"Canonical Dynamics: Equilibrium Phase-Space Distributions","volume":"31","author":"Hoover","year":"1985","journal-title":"Phys. Rev. A"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.1063\/1.467468","article-title":"Constant Pressure Molecular Dynamics Algorithms","volume":"101","author":"Martyna","year":"1994","journal-title":"J. Chem. Phys."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A Smooth Particle Mesh Ewald Method","volume":"103","author":"Essmann","year":"1995","journal-title":"J. Chem. Phys."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1016\/j.bpj.2015.08.015","article-title":"MDTraj: A Modern Open Library for the Analysis of Molecular Dynamics Trajectories","volume":"109","author":"McGibbon","year":"2015","journal-title":"Biophys. J."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1107\/S0567739476001873","article-title":"A Solution for the Best Rotation to Relate Two Sets of Vectors","volume":"32","author":"Kabsch","year":"1976","journal-title":"Acta Crystallogr. Sect. A"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"031910","DOI":"10.1103\/PhysRevE.65.031910","article-title":"Convergence of sampling in protein simulations","volume":"65","author":"Hess","year":"2002","journal-title":"Phys. Rev. E"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/12\/2156\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:37:16Z","timestamp":1782448636000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/12\/2156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":104,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["molecules31122156"],"URL":"https:\/\/doi.org\/10.3390\/molecules31122156","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]}}}