title: QSAR analysis of nicotinamidic compounds and design of potential Bruton's tyrosine kinase (Btk) inhibitors.
abstract: Bruton's tyrosine kinase (Btk) is an important enzyme in B-lymphocyte development and differentiation. Furthermore, Btk expression is considered essential for the proliferation and survival of these cells. Btk inhibition has become an attractive strategy for treating autoimmune diseases, B-cell leukemia, and lymphomas. With the objective of proposing new candidates for Btk inhibitors, we applied receptor-dependent four-dimensional quantitative structure-activity relationship (QSAR) methodology to a series of 96 nicotinamide analogs useful as Btk modulators. The QSAR models were developed using 71 compounds, the training set, and externally validated using 25 compounds, the test set. The conformations obtained by molecular dynamics simulation were overlapped in a virtual three-dimensional cubic box comprised of 2 and 5 Å cells, according to the six trial alignments. The models were generated by combining genetic function approximation and partial least squares regression technique. The analyses suggest that Model 1a yields the best results. The best equation shows [Formula: see text], r(2) = .743, RMSEC = .831, RMSECV = .879. Given the importance of the Tyr551, this residue could become a strategic target for the design of novel Btk inhibitors with improved potency. In addition, the good potency predicted for the proposed M2 compound indicates this compound as a potential Btk inhibitor candidate.
authors: a Department of Chemistry , Federal University of Lavras , P.O. Box 3037, 37200-000 Lavras , MG , Brazil.
authors: Letícia
authors: L
authors: Santos-Garcia
authors: a Department of Chemistry , Federal University of Lavras , P.O. Box 3037, 37200-000 Lavras , MG , Brazil.
authors: Letícia C
authors: LC
authors: Assis
authors: a Department of Chemistry , Federal University of Lavras , P.O. Box 3037, 37200-000 Lavras , MG , Brazil.
authors: Daniela R
authors: DR
authors: Silva
authors: a Department of Chemistry , Federal University of Lavras , P.O. Box 3037, 37200-000 Lavras , MG , Brazil.
authors: Teodorico C
authors: TC
authors: Ramalho
authors: a Department of Chemistry , Federal University of Lavras , P.O. Box 3037, 37200-000 Lavras , MG , Brazil.
authors: Elaine F F
authors: EF
authors: da Cunha
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D015195:Drug Design; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009536:Niacinamide / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase
keywords: Bruton’s tyrosine kinase; QSAR; nicotinamide