Preclinical and phase I studies of KA2237, a selective and potent inhibitor of PI3K β/δ in relapsed refractory B cell lymphoma.

PI3-kinase p110δ is mainly expressed in lymphocytes and is an attractive therapeutic target in B cell lymphomas. Targeting p110β may further suppress tumor growth and overcome escape mechanisms. KA2237 is an oral, potent, dual p110β/p110δ inhibitor.

Exhaustive Repertoire of Druggable Cavities at Protein-Protein Interfaces of Known Three-Dimensional Structure.

Protein-protein interactions (PPIs) offer the unique opportunity to tailor ligands aimed at specifically stabilizing or disrupting the corresponding interfaces and providing a safer alternative to conventional ligands targeting monomeric macromolecules. Selecting biologically relevant protein-protein interfaces for either stabilization or disruption by small molecules is usually biology-driven on a case-by-case basis and does not follow a structural rationale that could be applied to an entire interactome. We herewith provide a first step to the latter goal by using a fully automated and structure-based workflow, applicable to any PPI of known three-dimensional (3D) structure, to identify and prioritize druggable cavities at and nearby PPIs of pharmacological interest.

Unsupervised Classification of G-Protein Coupled Receptors and Their Conformational States Using IChem Intramolecular Interaction Patterns.

Over the past decade, the ever-growing structural information on G-protein coupled receptors (GPCRs) has revealed the three-dimensional (3D) characteristics of a receptor structure that is competent for G-protein binding. Structural markers are now commonly used to distinguish GPCR functional states, especially when analyzing molecular dynamics simulations. In particular, the position of the sixth helix within the seven transmembrane domains (TMs) is directly related to the coupling of the G-protein.

All in One: Cavity Detection, Druggability Estimate, Cavity-Based Pharmacophore Perception, and Virtual Screening.

Discovering the very first ligands of pharmacologically important targets in a fast and cost-efficient manner is an important issue in drug discovery. In the absence of structural information on either endogenous or synthetic ligands, computational chemists classically identify the very first hits by docking compound libraries to a binding site of interest, with well-known biases arising from the usage of scoring functions. We herewith propose a novel computational method tailored to ligand-free protein structures and consisting in the generation of simple cavity-based pharmacophores to which potential ligands could be aligned by the use of a smooth Gaussian function.

Structure-Based Detection of Orthosteric and Allosteric Pockets at Protein-Protein Interfaces.

Protein-protein interfaces represent challenging but very promising targets to discover novel drugs with exquisite specificity profiles. We herewith chart for the first time all biologically relevant protein-protein interfaces of known X-ray structure and detect potentially druggable cavities at and nearby the interface. These cavities are then converted in simple 3D pharmacophore queries for identifying potential modulators (inhibitors, stabilizers) of druggable interfaces.

Improving Prediction of Metabolic Clearance Using Quantitative Extrapolation of Results Obtained From Human Hepatic Micropatterned Cocultures Model and by Considering the Impact of Albumin Binding.

The objective was to compare, with the same data set, the predictive performance of 3 in vitro assays of hepatic clearance (CL), namely, micropatterned cocultures (also referring to HepatoPac) and suspension as well as monolayer hepatocytes to define which assay is the most accurate. Furthermore, existing in vitro-to-in vivo extrapolation (IVIVE) methods were challenged to verify which method is the most predictive (i.e.

IChem: A Versatile Toolkit for Detecting, Comparing, and Predicting Protein-Ligand Interactions.

Structure-based ligand design requires an exact description of the topology of molecular entities under scrutiny. IChem is a software package that reflects the many contributions of our research group in this area over the last decade. It facilitates and automates many tasks (e.

Ranking docking poses by graph matching of protein-ligand interactions: lessons learned from the D3R Grand Challenge 2.

A novel docking challenge has been set by the Drug Design Data Resource (D3R) in order to predict the pose and affinity ranking of a set of Farnesoid X receptor (FXR) agonists, prior to the public release of their bound X-ray structures and potencies. In a first phase, 36 agonists were docked to 26 Protein Data Bank (PDB) structures of the FXR receptor, and next rescored using the in-house developed GRIM method. GRIM aligns protein-ligand interaction patterns of docked poses to those of available PDB templates for the target protein, and rescore poses by a graph matching method.

Docking pose selection by interaction pattern graph similarity: application to the D3R grand challenge 2015.

High affinity ligands for a given target tend to share key molecular interactions with important anchoring amino acids and therefore often present quite conserved interaction patterns. This simple concept was formalized in a topological knowledge-based scoring function (GRIM) for selecting the most appropriate docking poses from previously X-rayed interaction patterns. GRIM first converts protein-ligand atomic coordinates (docking poses) into a simple 3D graph describing the corresponding interaction pattern.

IChemPIC: A Random Forest Classifier of Biological and Crystallographic Protein-Protein Interfaces.

Protein-protein interactions are becoming a major focus of academic and pharmaceutical research to identify low molecular weight compounds able to modulate oligomeric signaling complexes. As the number of protein complexes of known three-dimensional structure is constantly increasing, there is a need to discard biologically irrelevant interfaces and prioritize those of high value for potential druggability assessment. A Random Forest model has been trained on a set of 300 protein-protein interfaces using 45 molecular interaction descriptors as input.

Analysis of Glycogen Synthase Kinase Inhibitors That Regulate Cytochrome P450 Expression in Primary Human Hepatocytes by Activation of β-Catenin, Aryl Hydrocarbon Receptor and Pregnane X Receptor Signaling.

Cytochrome P450 (CYP) expression and activity are not homogeneous in the liver lobules. Indeed, CYPs are mainly expressed and induced in centrilobular hepatocytes. The wingless-type MMTV integration site family (WNT)/β-catenin pathway was identified as a major regulator of this zonal organization.

Game on, science - how video game technology may help biologists tackle visualization challenges.

The video games industry develops ever more advanced technologies to improve rendering, image quality, ergonomics and user experience of their creations providing very simple to use tools to design new games. In the molecular sciences, only a small number of experts with specialized know-how are able to design interactive visualization applications, typically static computer programs that cannot easily be modified. Are there lessons to be learned from video games? Could their technology help us explore new molecular graphics ideas and render graphics developments accessible to non-specialists? This approach points to an extension of open computer programs, not only providing access to the source code, but also delivering an easily modifiable and extensible scientific research tool.

Enantioselective organocatalytic aldol reaction of ynones and its synthetic applications.

[Structure: see text] For the first time, unmodified ynones were used in organocatalytic asymmetric aldol reactions delivering monoprotected anti-alpha,beta-dihydroxyynones in high yields, dr's up to 19:1, and ee's up to 95%. These products can be either reduced to afford enantioenriched unsaturated anti,anti-triol or cyclized using a novel intramolecular phosphine-catalyzed alpha-addition to the ynone. This organocatalytic sequential aldol-cyclization process provides a concise entry to unusual enantioenriched oxygenated heterocycles, which can be used for subsequent structural manipulations.

Pd(II)-catalyzed cascade Wacker-Heck reaction: chemoselective coupling of two electron-deficient reactants.

A novel palladium(II)-catalyzed oxy-carbopalladation process was developed allowing for the orchestrated union of hydroxy ynones with ethyl acrylate, two electron-deficient reactants. With beta-hydroxy ynones, this cascade Wacker-Heck process gave access to highly functionalized tri- or tetrasubstituted dihydropyranones featuring an unusual dienic system. For diastereomerically pure and for enantioenriched beta-hydroxyynones, these reactions proceed without affecting the stereochemical integrity of the existing stereocenters.