ABSTRACT
Reported here is a rational approach for the selection of solvents intended for use in physical form screening based on a novel chemoinformatics analysis of solvent properties. A comprehensive assessment of eight clustering methods was carried out on a series of 94 solvents described by calculated molecular descriptors using the clusterSim package in R. The effectiveness of clustering methods was evaluated using a range of statistical measures as well as increasing efficiency of solid form discovery using a cluster-based solvent selection approach. Multidimensional scaling was used to illustrate cluster analysis on a two-dimensional solvent map. The map presented here is a valuable tool to aid efficient solvent selection in physical form screens. This tool is equally applicable to any scientific area which requires a solubility dependent decision on solvent choice.
Subject(s)
Informatics/methods , Small Molecule Libraries/chemistry , Solvents/chemistry , Models, Molecular , Molecular ConformationABSTRACT
The Ser/Thr protein kinase MAPKAP kinase2 (MAPKAPK2 or MK2) plays an important role in inflammation. A comparison of several crystal structures of MK2 shows that differences in active and inactive conformations result in large part from structural variations within the conformations of the glycine rich loop (p-loop) regions. We propose the most preferred binding conformation of two classes of MK2 inhibitors and suggest plausible critical interactions with active site residues. The predicted binding conformations of the two classes of MK2 inhibitors depend upon their orientation in the active site and activities were well correlated with the sum of D and G scores. A qualitative relationship between the sum of D and G scores and the measured activities can be demonstrated.
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/chemistry , Models, Molecular , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/chemistry , Pyrazoles/metabolism , Pyrazoles/pharmacology , Pyridines/metabolism , Pyridines/pharmacology , Adenosine Triphosphate/metabolism , Amino Acid Motifs , Amino Acid Sequence , Catalytic Domain , Computer Simulation , Conserved Sequence , Crystallography, X-Ray , Glycine , Intracellular Signaling Peptides and Proteins/metabolism , Ligands , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Secondary , Pyrazoles/chemistry , Pyridines/chemistry , Reproducibility of ResultsABSTRACT
Oxazolidinones are known to inhibit protein biosynthesis and act against a wide spectrum of gram-positive bacteria. A new investigational oxazolidinone, ranbezolid, inhibited bacterial protein synthesis in Staphylococcus aureus and Staphylococcus epidermidis. In S. epidermidis, ranbezolid showed inhibition of cell wall and lipid synthesis and a dose-dependent effect on membrane integrity. A kill-kinetics study showed that ranbezolid was bactericidal against S. epidermidis. In vitro translation of the luciferase gene done using bacterial and mammalian ribosomes indicated that ranbezolid specifically inhibited the bacterial ribosome. Molecular modeling studies revealed that both linezolid and ranbezolid fit in similar manners the active site of ribosomes, with total scores, i.e., theoretical binding affinities after consensus, of 5.2 and 6.9, respectively. The nitrofuran ring in ranbezolid is extended toward C2507, G2583, and U2584, and the nitro group forms a hydrogen bond from the base of G2583. The interaction of ranbezolid with the bacterial ribosomes clearly helps to elucidate its potent activity against the target pathogen.
Subject(s)
Anti-Bacterial Agents/pharmacology , Furans/pharmacology , Oxazoles/pharmacology , Protein Synthesis Inhibitors/pharmacology , Ribosomes/drug effects , Staphylococcus aureus/drug effects , Staphylococcus epidermidis/drug effects , Acetamides/pharmacology , Cell Membrane Permeability/drug effects , Linezolid , Oxazolidinones/pharmacology , Protein Biosynthesis/drug effects , Ribosomes/metabolism , Transcription, Genetic/drug effectsABSTRACT
Protein kinases are involved in many diseases like cancer, inflammation, cardiovascular disease, and diabetes. They have become attractive target classes for drug development, making kinase inhibitors as important class of therapeutics. The success of small-molecule ATP-competitive kinase inhibitors such as Gleevec, Iressa, and Tarceva has attracted much attention in the recent past. Kinases make use of ATP for phosphorylation of a specific residue(s) on their protein substrates. More than 400 X-ray structures of about 70 different kinases are publicly available. These structures provide insights into selectivity and mechanisms of inhibition. However, prediction of binding specificity of kinase inhibitors based on structural information alone appears to be insufficient. Here, we will review these observations to gain insights into the rules that govern protein kinase inhibitor selectivity.
