{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T07:03:31Z","timestamp":1788246211546,"version":"build-2803163510"},"reference-count":60,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deputyship for Research &amp; Innovation, Ministry of Education in Saudi Arabia","award":["375213500"],"award-info":[{"award-number":["375213500"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A new series of 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine linked sulfonamide derivatives 12a\u2013n was designed and synthesized according to the structure of well-established V600EBRAF inhibitors. The terminal sulfonamide moiety was linked to the pyrimidine ring via either ethylamine or propylamine bridge. The designed series was tested at fixed concentration (1 \u00b5M) against V600EBRAF, finding that 12e, 12i and 12l exhibited the strongest inhibitory activity among all target compounds and 12l had the lowest IC50 of 0.49 \u00b5M. They were further screened on NCI 60 cancer cell lines to reveal that 12e showed the most significant growth inhibition against multiple cancer cell lines. Therefore, cell cycle analysis of 12e was conducted to investigate the effect on cell cycle progression. Finally, virtual docking studies was performed to gain insights for the plausible binding modes of vemurafenib, 12i, 12e and 12l.<\/jats:p>","DOI":"10.3390\/ijms221910491","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T21:38:09Z","timestamp":1632865089000},"page":"10491","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Design, Synthesis and Anticancer Profile of New 4-(1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine-Linked Sulfonamide Derivatives with V600EBRAF Inhibitory Effect"],"prefix":"10.3390","volume":"22","author":[{"given":"Mohammed S.","family":"Abdel-Maksoud","sequence":"first","affiliation":[{"name":"Pharmaceutical and Drug Industries Research Division, Medicinal & Pharmaceutical Chemistry Department, National Research Centre (ID: 60014618), Dokki, Giza 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3912-1021","authenticated-orcid":false,"given":"Ahmed A. B.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasha M.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Pharmaceutical and Drug Industries Research Division, Medicinal & Pharmaceutical Chemistry Department, National Research Centre (ID: 60014618), Dokki, Giza 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9035-5638","authenticated-orcid":false,"given":"Mohamed A.","family":"Abdelgawad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7367-7678","authenticated-orcid":false,"given":"Garri","family":"Chilingaryan","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology of NAS, Yerevan 0014, Armenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4025-8586","authenticated-orcid":false,"given":"Samy","family":"Selim","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72341, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S.","family":"Abdel-Bakky","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9820-4022","authenticated-orcid":false,"given":"Mohammad M.","family":"Al-Sanea","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.ejps.2018.08.030","article-title":"Design, synthesis and biological screening of 2-aminobenzamides as selective hdac3 inhibitors with promising anticancer effects","volume":"124","author":"Trivedi","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105045","DOI":"10.1016\/j.ejps.2019.105045","article-title":"Design, synthesis and anticancer evaluation of novel 1,3-benzodioxoles and 1,4-benzodioxines","volume":"139","author":"Hassan","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ejps.2016.03.022","article-title":"Novel fluorinated docetaxel analog for anti-hepatoma: Molecular docking and biological evaluation","volume":"88","author":"Hao","year":"2016","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"497","DOI":"10.2147\/DDDT.S237957","article-title":"Design, synthesis and biological evaluation of new hdac1 and hdac2 inhibitors endowed with ligustrazine as a novel cap moiety","volume":"14","author":"Gotina","year":"2020","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1084\/jem.20051848","article-title":"The braf-mapk signaling pathway is essential for cancer-immune evasion in human melanoma cells","volume":"203","author":"Sumimoto","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1097\/CCO.0b013e3282f5271c","article-title":"The mapk pathway in melanoma","volume":"20","author":"Fecher","year":"2008","journal-title":"Curr. Opin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.ejmech.2014.11.023","article-title":"Synthesis and biological evaluation of new pyrazol-4-ylpyrimidine derivatives as potential ros1 kinase inhibitors","volume":"90","author":"Abdelazem","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"115525","DOI":"10.1016\/j.bmc.2020.115525","article-title":"Sulfonamide-based 4-anilinoquinoline derivatives as novel dual aurora kinase (aurka\/b) inhibitors: Synthesis, biological evaluation and in silico insights","volume":"28","author":"Elkamhawy","year":"2020","journal-title":"Bioorg. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/nature00766","article-title":"Mutations of the braf gene in human cancer","volume":"417","author":"Davies","year":"2002","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/S1535-6108(02)00089-2","article-title":"A genome-based strategy uncovers frequent braf mutations in melanoma","volume":"2","author":"Pollock","year":"2002","journal-title":"Cancer Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5705","DOI":"10.1200\/JCO.2008.18.0786","article-title":"Wild-type braf is required for response to panitumumab or cetuximab in metastatic colorectal cancer","volume":"26","author":"Martini","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5399","DOI":"10.1210\/jc.2003-030838","article-title":"Braf mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas","volume":"88","author":"Nikiforova","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_14","first-page":"1454","article-title":"High prevalence of braf mutations in thyroid cancer: Genetic evidence for constitutive activation of the ret\/ptc-ras-braf signaling pathway in papillary thyroid carcinoma","volume":"63","author":"Kimura","year":"2003","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/path.1511","article-title":"Braf mutations are associated with some histological types of papillary thyroid carcinoma","volume":"202","author":"Trovisco","year":"2004","journal-title":"J. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1158\/0008-5472.CAN-08-3563","article-title":"Antitumor efficacy of the novel raf inhibitor gdc-0879 is predicted by brafv600e mutational status and sustained extracellular signal-regulated kinase\/mitogen-activated protein kinase pathway suppression","volume":"69","author":"Hoeflich","year":"2009","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19936","DOI":"10.1073\/pnas.0707498104","article-title":"Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling","volume":"104","author":"McDermott","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/nature04304","article-title":"Braf mutation predicts sensitivity to mek inhibition","volume":"439","author":"Solit","year":"2006","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/S0092-8674(04)00215-6","article-title":"Mechanism of activation of the raf-erk signaling pathway by oncogenic mutations of b-raf","volume":"116","author":"Wan","year":"2004","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2338","DOI":"10.1158\/0008-5472.CAN-03-3433","article-title":"V599eb-raf is an oncogene in melanocytes","volume":"64","author":"Wellbrock","year":"2004","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1056\/NEJMoa1103782","article-title":"Improved survival with vemurafenib in melanoma with braf v600e mutation","volume":"364","author":"Chapman","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.bcp.2013.11.013","article-title":"Emerging insights into resistance to braf inhibitors in melanoma","volume":"87","author":"Bucheit","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"142","DOI":"10.2174\/0929867322666151006093623","article-title":"Ros1 kinase inhibitors for molecular-targeted therapies","volume":"23","author":"Abdelazem","year":"2016","journal-title":"Curr. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1038\/nrd2130","article-title":"Discovery and development of sorafenib: A multikinase inhibitor for treating cancer","volume":"5","author":"Wilhelm","year":"2006","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3129","DOI":"10.1158\/1535-7163.MCT-08-0013","article-title":"Preclinical overview of sorafenib, a multikinase inhibitor that targets both raf and vegf and pdgf receptor tyrosine kinase signaling","volume":"7","author":"Wilhelm","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/nrd3847","article-title":"Vemurafenib: The first drug approved for braf-mutant cancer","volume":"11","author":"Bollag","year":"2012","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3989","DOI":"10.1016\/j.bmc.2017.05.044","article-title":"Design, synthesis and biological evaluation of sulfonamide-substituted diphenylpyrimidine derivatives (sul-dppys) as potent focal adhesion kinase (fak) inhibitors with antitumor activity","volume":"25","author":"Qu","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.ejmech.2017.04.037","article-title":"Design and synthesis of sulfonamide-substituted diphenylpyrimidines (sfa-dppys) as potent bruton\u2019s tyrosine kinase (btk) inhibitors with improved activity toward b-cell lymphoblastic leukemia","volume":"135","author":"Liu","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1517\/17425255.2013.794220","article-title":"Clinical development of dabrafenib in braf mutant melanoma and other malignancies","volume":"9","author":"Gibney","year":"2013","journal-title":"Expert. Opin. Drug Metab. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1016\/j.bmcl.2013.02.007","article-title":"N-substituted azaindoles as potent inhibitors of cdc7 kinase","volume":"23","author":"Bryan","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_31","first-page":"519","article-title":"Novel benzimidazole derivatives as expected anticancer agents","volume":"68","author":"Nofal","year":"2011","journal-title":"Acta Pol. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.ejmech.2009.09.032","article-title":"Pyrazoline bearing benzimidazoles: Search for anticancer agent","volume":"45","author":"Shaharyar","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2949","DOI":"10.1016\/j.ejmech.2010.03.022","article-title":"Synthesis and anticancer activity of some novel 2-substituted benzimidazole derivatives","volume":"45","author":"Refaat","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.bmcl.2013.12.005","article-title":"Synthesis and in vitro antitumor evaluation of primary amine substituted quinazoline linked benzimidazole","volume":"24","author":"Paul","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2937","DOI":"10.1016\/j.bmc.2010.02.037","article-title":"Antiviral activity of benzimidazole derivatives. Ii. Antiviral activity of 2-phenylbenzimidazole derivatives","volume":"18","author":"Tonelli","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1070\/RCR4832","article-title":"Benzimidazole nucleosides: Antiviral and antitumour activities and methods of synthesis","volume":"87","author":"Kharitonova","year":"2018","journal-title":"Russ. Chem. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4790","DOI":"10.1021\/jm060330f","article-title":"Synthesis and anti-hepatitis b virus activity of novel benzimidazole derivatives","volume":"49","author":"Li","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1128\/AAC.19.1.29","article-title":"Antibacterial and antifungal activities of benzimidazole and benzoxazole derivatives","volume":"19","author":"Elnima","year":"1981","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12422","DOI":"10.1039\/c3ra46304d","article-title":"Benzimidazole-biologically attractive scaffold for protein kinase inhibitors","volume":"4","author":"Singla","year":"2014","journal-title":"Rsc. Adv."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0304-4017(97)00107-6","article-title":"Anthelmintic resistance","volume":"72","author":"Waller","year":"1997","journal-title":"Vet. Parasitol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S1090-0233(05)80005-X","article-title":"Modes of action of anthelmintic drugs","volume":"154","author":"Martin","year":"1997","journal-title":"Vet. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1021\/ja01468a052","article-title":"Antiparasitic drugs. Iv. 2-(4\u2032-thiazolyl)-benzimidazole, a new anthelmintic","volume":"83","author":"Brown","year":"1961","journal-title":"J. Am. Chem. Soc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6877","DOI":"10.1021\/acs.jmedchem.1c00230","article-title":"Discovery of new imidazo[2,1-b]thiazole derivatives as potent pan-raf inhibitors with promising in vitro and in vivo anti-melanoma activity","volume":"64","author":"Lee","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.ejmech.2017.01.006","article-title":"Design and synthesis of new raf kinase-inhibiting antiproliferative quinoline derivatives. Part 2: Diarylurea derivatives","volume":"127","author":"Khan","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1007\/s00044-016-1529-7","article-title":"Broad-spectrum antiproliferative activity of a series of 6-(4-fluorophenyl)-5-(2-substituted pyrimidin-4-yl)imidazo[2,1-b]thiazole derivatives","volume":"25","author":"Kwak","year":"2016","journal-title":"Med. Chem. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"103349","DOI":"10.1016\/j.bioorg.2019.103349","article-title":"Design, synthesis, and anticancer activity of imidazo[2,1-b]oxazole-based raf kinase inhibitors","volume":"93","author":"Ammar","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"113277","DOI":"10.1016\/j.ejmech.2021.113277","article-title":"Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl) pyrimidine-based derivatives as dual brafv600e\/p38\u03b1 inhibitors","volume":"215","author":"Ali","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"115493","DOI":"10.1016\/j.bmc.2020.115493","article-title":"Design and synthesis of novel pyrrolo[2,3-b]pyridine derivatives targeting (v600e)braf","volume":"28","author":"Ali","year":"2020","journal-title":"Bioorg. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1021\/acsmedchemlett.0c00094","article-title":"Benzofuran-based carboxylic acids as carbonic anhydrase inhibitors and antiproliferative agents against breast cancer","volume":"11","author":"Eldehna","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_50","unstructured":"Vogel, A.I., Furniss, B.S., Hannaford, A.J., Smith, P.W., and Tatchell, A.R. (1989). Vogel\u2019s Textbook of Practical Organic Chemistry, Longman Scientific & Technical."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1080\/14756366.2020.1773814","article-title":"Novel [(n-alkyl-3-indolylmethylene)hydrazono]oxindoles arrest cell cycle and induce cell apoptosis by inhibiting cdk2 and bcl-2: Synthesis, biological evaluation and in silico studies","volume":"35","author":"Almahli","year":"2020","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The protein data bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_53","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_54","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1002\/jcc.540150503","article-title":"Icm\u2014A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation","volume":"15","author":"Abagyan","year":"1994","journal-title":"J. Comput. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1007\/s10822-021-00389-3","article-title":"Improving virtual screening results with mm\/gbsa and mm\/pbsa rescoring","volume":"35","author":"Sahakyan","year":"2021","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The amber biomolecular simulation programs","volume":"26","author":"Case","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_57","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_58","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/BF02769620","article-title":"Markov chain monte carlo methods for conditioning a permeability field to pressure data","volume":"29","author":"Oliver","year":"1997","journal-title":"Math. Geol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.cplett.2003.10.013","article-title":"Self-guided langevin dynamics simulation method","volume":"381","author":"Wu","year":"2003","journal-title":"Chem. Phys. Lett."},{"key":"ref_60","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."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10491\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:06:39Z","timestamp":1760166399000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10491"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,28]]},"references-count":60,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910491"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910491","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,28]]}}}