Large-Scale Prediction of the ARS Family Inhibitors of the Oncogenic KRASG12C Mutant
| Autor: | A. V. Popinako, Maria G. Khrenova, A. M. Kulakova |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Molecular switch
0303 health sciences Molecular model Cell growth Stereochemistry Computer science Point mutation Mutant medicine.disease_cause Dissociation constant 03 medical and health sciences 0302 clinical medicine Covalent bond 030220 oncology & carcinogenesis Cancer cell medicine KRAS 030304 developmental biology |
| Zdroj: | Large-Scale Scientific Computing ISBN: 9783030410315 LSSC |
| Popis: | The KRAS protein is a molecular switch that activates cellular processes, like cell growth and differentiation. The G12C point mutation of the KRAS is found in various cancer cells. It results in the accretion of the GTP-bound active form thus accelerating downstream signalling pathways. Recently ARS family of compounds was suggested as selective covalent inhibitors of the KRASG12C. The most prospective ARS-853 has IC\(_{50}\) = 1.6 \(\upmu \)M that is too large for the medicinal applications. We demonstrate that calculated dissociation constants K\(_\mathrm{d}\) are proportional to the experimental IC\(_{50}\) values and can be utilized as a measure of the inhibitor potency. Using molecular modeling tools we suggest a set of novel compounds with the predicted IC\(_{50}\) values more than an order of magnitude lower than that of the ARS-853. |
| Databáze: | OpenAIRE |
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