{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T04:36:13Z","timestamp":1775277373156,"version":"3.50.1"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T00:00:00Z","timestamp":1650931200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010679","name":"Pasteur Institute of Iran","doi-asserted-by":"publisher","award":["583"],"award-info":[{"award-number":["583"]}],"id":[{"id":"10.13039\/501100010679","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alexander von Humboldt Foundation fellowship"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>K-Ras activating mutations are significantly associated with tumor progression and aggressive metastatic behavior in various human cancers including pancreatic cancer. So far, despite a large number of concerted efforts, targeting of mutant-type K-Ras has not been successful. In this regard, we aimed to target this oncogene by a combinational approach consisting of small peptide and small molecule inhibitors. Based on a comprehensive analysis of structural and physicochemical properties of predominantly K-Ras mutants, an anti-cancer peptide library and a small molecule library were screened to simultaneously target oncogenic mutations and functional domains of mutant-type K-Ras located in the P-loop, switch I, and switch II regions. The selected peptide and small molecule showed notable binding affinities to their corresponding binding sites, and hindered the growth of tumor cells carrying K-Ras<jats:sup>G12D<\/jats:sup>and K-Ras<jats:sup>G12C<\/jats:sup>mutations. Of note, the expression of K-Ras downstream genes (i.e., CTNNB1, CCND1) was diminished in the treated Kras-positive cells. In conclusion, our combinational platform signifies a new potential for blockade of oncogenic K-Ras and thereby prevention of tumor progression and metastasis. However, further validations are still required regarding the<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>efficacy and safety of this approach.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009962","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T18:02:09Z","timestamp":1650996129000},"page":"e1009962","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Multi-targeting of K-Ras domains and mutations by peptide and small molecule inhibitors"],"prefix":"10.1371","volume":"18","author":[{"given":"Mansour","family":"Poorebrahim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad Foad","family":"Abazari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leila","family":"Moradi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Behzad","family":"Shahbazi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reza","family":"Mahmoudi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0715-294X","authenticated-orcid":true,"given":"Hourieh","family":"Kalhor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2285-2592","authenticated-orcid":true,"given":"Hassan","family":"Askari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6588-9774","authenticated-orcid":true,"given":"Ladan","family":"Teimoori-Toolabi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,4,26]]},"reference":[{"issue":"11","key":"pcbi.1009962.ref001","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/nrc3106","article-title":"RAS oncogenes: weaving a tumorigenic web","volume":"11","author":"Y Pylayeva-Gupta","year":"2011","journal-title":"Nature reviews Cancer"},{"issue":"13","key":"pcbi.1009962.ref002","doi-asserted-by":"crossref","first-page":"5219","DOI":"10.1021\/jm3017706","article-title":"Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators","volume":"56","author":"Y Wang","year":"2013","journal-title":"Journal of medicinal chemistry"},{"issue":"38","key":"pcbi.1009962.ref003","doi-asserted-by":"crossref","first-page":"4914","DOI":"10.1038\/onc.2014.416","article-title":"Oncogenic KRAS signalling promotes the Wnt\/\u03b2-catenin pathway through LRP6 in colorectal cancer","volume":"34","author":"E Lemieux","year":"2015","journal-title":"Oncogene"},{"issue":"1","key":"pcbi.1009962.ref004","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrc969","article-title":"Targeting RAS signalling pathways in cancer therapy","volume":"3","author":"J. Downward","year":"2003","journal-title":"Nature reviews Cancer"},{"issue":"14","key":"pcbi.1009962.ref005","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1093\/jnci\/93.14.1062","article-title":"Blocking oncogenic Ras signaling for cancer therapy","volume":"93","author":"AA Adjei","year":"2001","journal-title":"Journal of the National Cancer Institute"},{"issue":"10","key":"pcbi.1009962.ref006","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1158\/0008-5472.CAN-11-2612","article-title":"A comprehensive survey of Ras mutations in cancer","volume":"72","author":"IA Prior","year":"2012","journal-title":"Cancer research"},{"issue":"11","key":"pcbi.1009962.ref007","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrd.2016.139","article-title":"Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design","volume":"15","author":"JM Ostrem","year":"2016","journal-title":"Nature reviews Drug discovery"},{"issue":"3","key":"pcbi.1009962.ref008","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1177\/1947601911412376","article-title":"Therapeutic strategies for targeting ras proteins","volume":"2","author":"S Gysin","year":"2011","journal-title":"Genes & cancer"},{"issue":"6","key":"pcbi.1009962.ref009","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.chembiol.2015.04.019","article-title":"Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions","volume":"22","author":"L Laraia","year":"2015","journal-title":"Chemistry & biology"},{"issue":"6","key":"pcbi.1009962.ref010","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1021\/mp500115x","article-title":"Design and applications of bispecific heterodimers: molecular imaging and beyond","volume":"11","author":"H Luo","year":"2014","journal-title":"Molecular pharmaceutics"},{"key":"pcbi.1009962.ref011","unstructured":"DeLano WL. The PyMOL molecular graphics system. http:\/\/pymol.org. 2002."},{"issue":"13","key":"pcbi.1009962.ref012","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014a visualization system for exploratory research and analysis","volume":"25","author":"EF Pettersen","year":"2004","journal-title":"Journal of computational chemistry"},{"issue":"2","key":"pcbi.1009962.ref013","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/protein\/8.2.127","article-title":"LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions","volume":"8","author":"AC Wallace","year":"1995","journal-title":"Protein Engineering, Design and Selection"},{"issue":"D1","key":"pcbi.1009962.ref014","doi-asserted-by":"crossref","first-page":"D837","DOI":"10.1093\/nar\/gku892","article-title":"CancerPPD: a database of anticancer peptides and proteins","volume":"43","author":"A Tyagi","year":"2014","journal-title":"Nucleic acids research"},{"issue":"1","key":"pcbi.1009962.ref015","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1021\/ci049714+","article-title":"ZINC\u2212 a free database of commercially available compounds for virtual screening","volume":"45","author":"JJ Irwin","year":"2005","journal-title":"Journal of chemical information and modeling"},{"key":"pcbi.1009962.ref016","article-title":"FAF-Drugs4: free ADME-tox filtering computations for chemical biology and early stages drug discovery","author":"D Lagorce","year":"2017","journal-title":"Bioinformatics"},{"issue":"2","key":"pcbi.1009962.ref017","doi-asserted-by":"crossref","first-page":"e0172217","DOI":"10.1371\/journal.pone.0172217","article-title":"Rational design of DKK3 structure-based small peptides as antagonists of Wnt signaling pathway and in silico evaluation of their efficiency","volume":"12","author":"M Poorebrahim","year":"2017","journal-title":"PLoS One"},{"issue":"5","key":"pcbi.1009962.ref018","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/nprot.2010.32","article-title":"The HADDOCK web server for data-driven biomolecular docking","volume":"5","author":"SJ De Vries","year":"2010","journal-title":"Nature protocols"},{"issue":"23","key":"pcbi.1009962.ref019","doi-asserted-by":"crossref","first-page":"3676","DOI":"10.1093\/bioinformatics\/btw514","article-title":"PRODIGY: a web server for predicting the binding affinity of protein\u2013protein complexes","volume":"32","author":"LC Xue","year":"2016","journal-title":"Bioinformatics"},{"issue":"6","key":"pcbi.1009962.ref020","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1093\/bioinformatics\/btt038","article-title":"SwarmDock: a server for flexible protein-protein docking","volume":"29","author":"M Torchala","year":"2013","journal-title":"Bioinformatics"},{"issue":"suppl_2","key":"pcbi.1009962.ref021","doi-asserted-by":"crossref","first-page":"W249","DOI":"10.1093\/nar\/gkr431","article-title":"Rosetta FlexPepDock web server\u2014high resolution modeling of peptide\u2013protein interactions","volume":"39","author":"N London","year":"2011","journal-title":"Nucleic acids research"},{"issue":"8","key":"pcbi.1009962.ref022","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1021\/ci300604z","article-title":"Lessons learned in empirical scoring with smina from the CSAR 2011 benchmarking exercise","volume":"53","author":"DR Koes","year":"2013","journal-title":"Journal of chemical information and modeling"},{"key":"pcbi.1009962.ref023","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1","author":"MJ Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"pcbi.1009962.ref024","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.bej.2019.02.014","article-title":"An engineered analog of insulin-like growth factor 1 with reduced immunogenicity and retained mitogenicity","volume":"145","author":"M Poorebrahim","year":"2019","journal-title":"Biochemical Engineering Journal"},{"issue":"4","key":"pcbi.1009962.ref025","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1097\/MPA.0b013e3181c15963","article-title":"Phenotype and genotype of pancreatic cancer cell lines","volume":"39","author":"EL Deer","year":"2010","journal-title":"Pancreas"},{"issue":"1","key":"pcbi.1009962.ref026","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1089\/cbr.2009.0643","article-title":"Selective suicide gene therapy of colon cancer cell lines exploiting fibroblast growth factor 18 promoter","volume":"25","author":"L Teimoori-Toolabi","year":"2010","journal-title":"Cancer Biother Radiopharm"},{"key":"pcbi.1009962.ref027","article-title":"The structural basis of oncogenic mutations G12, G13 and Q61 in small GTPase K-Ras4B","volume":"6","author":"S Lu","year":"2016","journal-title":"Scientific reports"},{"issue":"11","key":"pcbi.1009962.ref028","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nrd4389","article-title":"Drugging the undruggable RAS: mission possible?","volume":"13","author":"AD Cox","year":"2014","journal-title":"Nature reviews Drug discovery"},{"issue":"48","key":"pcbi.1009962.ref029","doi-asserted-by":"crossref","first-page":"7596","DOI":"10.1021\/bi5011317","article-title":"Structural effect of the Asp345a insertion in penicillin-binding protein 2 from penicillin-resistant strains of Neisseria gonorrhoeae","volume":"53","author":"A Fedarovich","year":"2014","journal-title":"Biochemistry"},{"key":"pcbi.1009962.ref030","article-title":"The role of shape complementarity in the protein-protein interactions","volume":"3","author":"Y Li","year":"2013","journal-title":"Scientific reports"},{"issue":"2","key":"pcbi.1009962.ref031","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/S0021-9258(18)54000-X","article-title":"GDP dissociation inhibitor prevents intrinsic and GTPase activating protein-stimulated GTP hydrolysis by the Rac GTP-binding protein","volume":"268","author":"TH Chuang","year":"1993","journal-title":"Journal of Biological Chemistry"},{"key":"pcbi.1009962.ref032","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.jtbi.2017.01.009","article-title":"In silico enhancement of the stability and activity of keratinocyte growth factor","volume":"418","author":"M Poorebrahim","year":"2017","journal-title":"Journal of theoretical biology"},{"key":"pcbi.1009962.ref033","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.critrevonc.2017.01.002","article-title":"The cornerstone K-RAS mutation in pancreatic adenocarcinoma: From cell signaling network, target genes, biological processes to therapeutic targeting","volume":"111","author":"N Jonckheere","year":"2017","journal-title":"Critical Reviews in Oncology\/Hematology"},{"issue":"3","key":"pcbi.1009962.ref034","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.str.2014.12.017","article-title":"Allosteric effects of the oncogenic RasQ61L mutant on Raf-RBD","volume":"23","author":"SK Fetics","year":"2015","journal-title":"Structure (London, England: 1993)"},{"issue":"1\u20133","key":"pcbi.1009962.ref035","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 settings","volume":"23","author":"CA Lipinski","year":"1997","journal-title":"Advanced drug delivery reviews"},{"issue":"12","key":"pcbi.1009962.ref036","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":"DF Veber","year":"2002","journal-title":"Journal of medicinal chemistry"},{"issue":"21","key":"pcbi.1009962.ref037","doi-asserted-by":"crossref","first-page":"3867","DOI":"10.1021\/jm000292e","article-title":"Prediction of drug absorption using multivariate statistics","volume":"43","author":"WJ Egan","year":"2000","journal-title":"Journal of medicinal chemistry"},{"issue":"18","key":"pcbi.1009962.ref038","doi-asserted-by":"crossref","first-page":"5488","DOI":"10.1080\/07391102.2019.1704880","article-title":"In-silico design of peptide inhibitors of K-Ras target in cancer disease","volume":"38","author":"M Ghufran","year":"2020","journal-title":"J Biomol Struct Dyn"},{"issue":"7","key":"pcbi.1009962.ref039","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1021\/acsmedchemlett.7b00128","article-title":"Crystal Structure of a Human K-Ras G12D Mutant in Complex with GDP and the Cyclic Inhibitory Peptide KRpep-2d","volume":"8","author":"S Sogabe","year":"2017","journal-title":"ACS Med Chem Lett"},{"issue":"9","key":"pcbi.1009962.ref040","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1016\/j.febslet.2009.11.046","article-title":"Arginine-rich cell-penetrating peptides","volume":"584","author":"N Schmidt","year":"2010","journal-title":"FEBS Lett"},{"key":"pcbi.1009962.ref041","doi-asserted-by":"crossref","DOI":"10.1038\/srep26278","article-title":"Topical delivery of protein and peptide using novel cell penetrating peptide imt-p8","volume":"6","author":"A Gautam","year":"2016","journal-title":"Scientific reports"},{"key":"pcbi.1009962.ref042","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/1479-5876-11-74","article-title":"In silico approaches for designing highly effective cell penetrating peptides","volume":"11","author":"A Gautam","year":"2013","journal-title":"Journal of translational medicine"},{"issue":"40","key":"pcbi.1009962.ref043","doi-asserted-by":"crossref","first-page":"4582","DOI":"10.1038\/sj.onc.1203818","article-title":"Structure and function of the C-terminal hypervariable region of K-Ras4B in plasma membrane targetting and transformation","volume":"19","author":"A Welman","year":"2000","journal-title":"Oncogene"},{"issue":"32","key":"pcbi.1009962.ref044","doi-asserted-by":"crossref","first-page":"7575","DOI":"10.1021\/bi900769j","article-title":"The hypervariable region of K-Ras4B is responsible for its specific interactions with calmodulin","volume":"48","author":"SJ Abraham","year":"2009","journal-title":"Biochemistry"},{"issue":"1","key":"pcbi.1009962.ref045","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1529\/biophysj.107.120501","article-title":"Molecular dynamics and principal components analysis of human telomeric quadruplex multimers","volume":"95","author":"S Haider","year":"2008","journal-title":"Biophysical journal"},{"issue":"25","key":"pcbi.1009962.ref046","doi-asserted-by":"crossref","first-page":"6140","DOI":"10.1002\/anie.201201358","article-title":"Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation","volume":"51","author":"Q Sun","year":"2012","journal-title":"Angewandte Chemie (International ed in English)"},{"issue":"3","key":"pcbi.1009962.ref047","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1021\/cb4007584","article-title":"Colloidal drug formulations can explain \"bell-shaped\" concentration-response curves","volume":"9","author":"SC Owen","year":"2014","journal-title":"ACS chemical biology"},{"issue":"6","key":"pcbi.1009962.ref048","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.21037\/tlcr-20-639","article-title":"Cyclin D1 expression in KRAS mutant non-small cell lung cancer-old wine into new skins","volume":"9","author":"KY Goh","year":"2020","journal-title":"Translational lung cancer research"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009962","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T15:59:18Z","timestamp":1675439958000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009962"}},"subtitle":[],"editor":[{"given":"Alexander","family":"MacKerell","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,4,26]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4,26]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009962","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,26]]}}}