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Molecular Modeling Studies on Carbazole Carboxamide Based BTK Inhibitors Using Docking and Structure-Based 3D-QSAR
- Source :
- International Journal of Molecular Sciences; Volume 19; Issue 4; Pages: 1244, International Journal of Molecular Sciences
- Publication Year :
- 2018
- Publisher :
- MDPI AG, 2018.
-
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.
- 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
Subjects
Details
- ISSN :
- 14220067
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....ce7edca2c9522e2fa8e97a6947319250