Exploration of Novel Inhibitors for Bruton's Tyrosine Kinase by 3D QSAR Modeling and Molecular Dynamics Simulation

PloS One
Rohit BaviKeun Woo Lee

Abstract

Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase which is expressed in most of the hematopoietic cells and plays an important role in many cellular signaling pathways. B cell malignancies are dependent on BCR signaling, thus making BTK an efficient therapeutic target. Over the last few years, significant efforts have been made in order to develop BTK inhibitors to treat B-cell malignancies, and autoimmunity or allergy/hypersensitivity but limited success has been achieved. Here in this study, 3D QSAR pharmacophore models were generated for Btk based on known IC50 values and experimental energy scores with extensive validations. The five features pharmacophore model, Hypo1, includes one hydrogen bond acceptor lipid, one hydrogen bond donor, and three hydrophobic features, which has the highest correlation coefficient (0.98), cost difference (112.87), and low RMS (1.68). It was further validated by the Fisher's randomization method and test set. The well validated Hypo1 was used as a 3D query to search novel Btk inhibitors with different chemical scaffold using high throughput virtual screening technique. The screened compounds were further sorted by applying ADMET properties, Lipinski's rule of five ...Continue Reading

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Citations

Oct 26, 2016·Journal of Computer-aided Molecular Design·Sergio Ruiz-Carmona, Xavier Barril
Jul 25, 2019·Journal of Biomolecular Structure & Dynamics·Sana GhayasRohit Bavi
Nov 7, 2020·Journal of Biomolecular Structure & Dynamics·Sagar BarageKeun Woo Lee
Nov 14, 2020·International Journal of Molecular Sciences·Andrey A BuglakBoris B Dzantiev

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Methods Mentioned

BETA
Feature Mapping

Software Mentioned

CHARMm
HypoGen
SwissParam
Discovery Studio
Chemscore
PubChem Structure
VMD
ChemSketch
GOLD
DS

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