Design of antitumor drugs targeting c-kit receptor by a new mixed ligand-structure based method

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Abstract

An important challenge, in the medicinal chemistry field, is the research of novel forceful drugs to overcome tumor-acquired resistance. The c-Kit tyrosine kinase receptor (TKR) represents a suitable target for the carcinogenesis control of gastro-intestinal stromal (GIST), leukemia, and mastocytosis tumors; nevertheless, several hotspot mutations of the protein limit the efficacy of a few clinical administered TKRs inhibitors. In this study, a new in silico protocol based on ligand and structure-based combined method is proposed, with the aim to identify a set of new c-Kit inhibitors able to complex c-Kit mutated proteins. A recent and freely available web-server DRUDIT is used for the ligand-based method. The protocol application allows for identifying a new generation of potential TKR inhibitors, which, in silico, complex the V654A and T670I mutated proteins and potentially overcome resistant mutations (D816H). The structure-based analysis is performed by Induced Fit Docking (IFD) studies. The comparison between the explored ligands and well-known drugs highlights the possibility to overcome tumor-acquired resistance. The best-selected structures (630705 and SML1348) provide valuable binding affinities with the mutated c-Kit forms (respectively T670I and V654A).
Lingua originaleEnglish
pagine (da-a)1-11
Numero di pagine11
RivistaJOURNAL OF MOLECULAR GRAPHICS & MODELLING
Volume100
Stato di pubblicazionePublished - 2020

All Science Journal Classification (ASJC) codes

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  • ???subjectarea.asjc.1600.1606???
  • ???subjectarea.asjc.1700.1704???
  • ???subjectarea.asjc.2500.2505???

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