Vertex Pharmaceuticals

About: Vertex Pharmaceuticals is a company organization based out in Boston, Massachusetts, United States. It is known for research contribution in the topics: Ivacaftor & Hepatitis C virus. The organization has 2135 authors who have published 2022 publications receiving 134750 citations. The organization is also known as: Vertex Pharmaceuticals Inc. & Vertex.

CORES: An automated method for generating three-dimensional models of protein/ligand complexes

Abstract: We describe a new, automated method for building 3D models of small-molecule ligands complexed with proteins. Modeling templates are constructed from frameworks (i.e., ring systems and linkers) of ligands extracted from 3D structures of ligands complexed with proteins that are structurally related to the target protein. These templates are typically substructures of the target ligand and are used to build models that constrain the ligand's conformation and binding orientation in the active site of the target protein. The practical utility of the method is shown by demonstrating that most ligands containing related frameworks bind protein kinases in the same orientation. Moreover, models for 15 of 19 cdk2/ligand complexes in the protein data bank built using our method deviate from the X-ray structure by less than 2 A (rms). Finally, we show that over 70% of small-molecule protein kinase inhibitors published in J. Med. Chem. since 1993 can be modeled using a template extracted from a 3D protein kinase structure in the protein data bank.

Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: an Industry Perspective.

Abstract: The effect of food on pharmacokinetic properties of drugs is a commonly observed occurrence affecting about 40% of orally administered drugs. Within the pharmaceutical industry, significant resources are invested to predict and characterize a clinically relevant food effect. Here, the predictive performance of physiologically based pharmacokinetic (PBPK) food effect models was assessed via de novo mechanistic absorption models for 30 compounds using controlled, pre-defined in vitro, and modeling methodology. Compounds for which absorption was known to be limited by intestinal transporters were excluded in this analysis. A decision tree for model verification and optimization was followed, leading to high, moderate, or low food effect prediction confidence. High (within 0.8- to 1.25-fold) to moderate confidence (within 0.5- to 2-fold) was achieved for most of the compounds (15 and 8, respectively). While for 7 compounds, prediction confidence was found to be low (> 2-fold). There was no clear difference in prediction success for positive or negative food effects and no clear relationship to the BCS category of tested drug molecules. However, an association could be demonstrated when the food effect was mainly related to changes in the gastrointestinal luminal fluids or physiology, including fluid volume, motility, pH, micellar entrapment, and bile salts. Considering these findings, it is recommended that appropriately verified mechanistic PBPK modeling can be leveraged with high to moderate confidence as a key approach to predicting potential food effect, especially related to mechanisms highlighted here.

Processes for preparing substituted pyrimidines and pyrimidine derivatives as inhibitors of protein kinases

Abstract: The present invention provides a facile process for the preparation of tri-and tetra-substituted pyrimidines. The process is useful for preparing inhibitors of protein kinases, especially Aurora kinase. These inhibitors are useful for treating or lessening the severity of Aurora-mediated diseases or conditions.