1. Molecular Modeling Studies on Carbazole Carboxamide Based BTK Inhibitors Using Docking and Structure-Based 3D-QSAR
- Author
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Zhipei Gao, Jingkang Shen, Yongli Du, and Rui Li
- Subjects
0301 basic medicine ,Quantitative structure–activity relationship ,Molecular model ,medicine.drug_class ,Broton’s tyrosine kinase (BTK) ,Carbazoles ,Quantitative Structure-Activity Relationship ,Carboxamide ,Pharmacology ,Molecular Docking Simulation ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Agammaglobulinaemia Tyrosine Kinase ,medicine ,Humans ,Bruton's tyrosine kinase ,rheumatoid arthritis (RA) ,Physical and Theoretical Chemistry ,Protein Kinase Inhibitors ,Molecular Biology ,Spectroscopy ,3D-QSAR ,carbazole carboxamide derivatives ,biology ,comparative molecular field analysis (CoMFA) ,Chemistry ,Carbazole ,Organic Chemistry ,comparative molecular similarity indices analysis (CoMSIA) ,Hydrogen Bonding ,General Medicine ,Protein-Tyrosine Kinases ,Computer Science Applications ,030104 developmental biology ,Docking (molecular) ,030220 oncology & carcinogenesis ,biology.protein ,Hydrophobic and Hydrophilic Interactions ,Tyrosine kinase ,Protein Binding - Abstract
Rheumatoid arthritis (RA) is the second common rheumatic immune disease with chronic, invasive inflammatory characteristics. Non-steroidal anti-inflammatory drugs (NSAIDs), slow-acting anti-rheumatic drugs (SAARDs), or glucocorticoid drugs can improve RA patients’ symptoms, but fail to cure. Broton’s tyrosine kinase (BTK) inhibitors have been proven to be an efficacious target against autoimmune indications and B-cell malignancies. Among the current 11 clinical drugs, only BMS-986142, classified as a carbazole derivative, is used for treating RA. To design novel and highly potent carbazole inhibitors, molecular docking and three dimensional quantitative structure–activity relationship (3D-QSAR) were applied to explore a dataset of 132 new carbazole carboxamide derivatives. The established comparative molecular field analysis (CoMFA) (q2 = 0.761, r2 = 0.933) and comparative molecular similarity indices analysis (CoMSIA) (q2 = 0.891, r2 = 0.988) models obtained high predictive and satisfactory values. CoMFA/CoMSIA contour maps demonstrated that bulky substitutions and hydrogen-bond donors were preferred at R1 and 1-position, respectively, and introducing hydrophilic substitutions at R1 and R4 was important for improving BTK inhibitory activities. These results will contribute to the design of novel and highly potent BTK inhibitors.
- Published
- 2018