Structure-based pharmacophore modelling for ErbB4-kinase inhibition: a systematic computational approach for small molecule drug discovery for breast cancer.
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引用次数: 0
Abstract
ErbB2 kinase is a key target in approximately 20% of breast cancer cases; however, ErbB2-positive cells may shift their dependence to ErbB4 upon developing resistance to ErbB2 inhibitors. Targeting ErbB4 presents a viable strategy to address this challenge. This study employs a comprehensive approach combining structure-based pharmacophore modelling, molecular docking, and MM-GBSA calculations to identify novel ErbB4 kinase inhibitors. Critical pharmacophoric features were extracted from the crystal structures of ErbB4-lapatinib, followed by virtual screening of the Chembl database to discover potential small molecule candidates. Furthermore, the ADMET profiles of 11 shortlisted candidates were assessed to verify their pharmacokinetic and toxicity properties, identifying Chembl310724, Chembl521284, and Chembl4168686 as promising inhibitors of ErbB4 kinase activity with the binding free energy (ΔGbind) values of -99.84, -89.42 and -86.06 kcal/mol, respectively. This integrated methodology not only enhances our understanding of ErbB4 inhibition but also sets a foundation for the rational design of targeted therapies addressing breast cancer with ErbB4 dependency.
期刊介绍:
SAR and QSAR in Environmental Research is an international journal welcoming papers on the fundamental and practical aspects of the structure-activity and structure-property relationships in the fields of environmental science, agrochemistry, toxicology, pharmacology and applied chemistry. A unique aspect of the journal is the focus on emerging techniques for the building of SAR and QSAR models in these widely varying fields. The scope of the journal includes, but is not limited to, the topics of topological and physicochemical descriptors, mathematical, statistical and graphical methods for data analysis, computer methods and programs, original applications and comparative studies. In addition to primary scientific papers, the journal contains reviews of books and software and news of conferences. Special issues on topics of current and widespread interest to the SAR and QSAR community will be published from time to time.