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Two-Track Virtual Screening Approach to Identify the Dual Inhibitors of Wild Type and C481S Mutant of Bruton's Tyrosine Kinase

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Title
Two-Track Virtual Screening Approach to Identify the Dual Inhibitors of Wild Type and C481S Mutant of Bruton's Tyrosine Kinase
Author(s)
Kim, Taeho; Kewon Kim; Inyoung Park; Sungwoo Hong; Park, Hwangseo
Publication Date
2022-09
Journal
JOURNAL OF CHEMICAL INFORMATION AND MODELING, v.62, no.18, pp.4500 - 4511
Publisher
AMER CHEMICAL SOC
Abstract
Bruton's tyrosine kinase (BTK) is responsible for the pathogenesis of various autoimmune diseases and chronic lymphocytic leukemia. However, the discovery of efficient medicines has seen limited success due to the constitutively active mutants that acquired the drug resistance. To disclose the dual inhibitors against the wild-type BTK and the problematic drug-resistant C481S mutant, a large chemical library was virtually screened with extensive molecular docking simulations using two target proteins. As a consequence of imposing the configurational restraint to make a hydrogen bond in the hinge region of BTK as well as modifying the ligand dehydration term in the scoring function, a total of 20 dual inhibitors were discovered with the range of the associated IC50 values from 2.5 to 15 mu M. All these dual inhibitors revealed the inhibitory activity against the C481S mutant to a comparable extent to that measured for the wild type. Among the new inhibitors, N-(3,5-dimethoxyphenyl)-6,7-dimethoxyquinazolin-4-amine (1) appeared to be most suitable as a starting point of the lead optimization due to the highest biochemical potency against the C481S mutant as well as the lowest molecular weight. To increase the potential of a drug candidate, 1 was modified into 6,7-dimethoxy-N-(pyridin-3-yl)quinazolin-4-amine (12) via chemical synthesis so as to possess better physicochemical properties without loss of the biochemical potency. 12 is suggested as a new effective molecular core from which numerous druggable dual inhibitors of the wild-type BTK and the C481S mutant would be derivatized.
URI
https://pr.ibs.re.kr/handle/8788114/12356
DOI
10.1021/acs.jcim.2c00623
ISSN
1549-9596
Appears in Collections:
Center for Catalytic Hydrocarbon Functionalizations(분자활성 촉매반응 연구단) > 1. Journal Papers (저널논문)
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