Extensive exploration of structure activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment merging and active learning.

The macrodomain contained in the SARS-CoV-2 non-structural protein 3 (NSP3) is required for viral pathogenesis and lethality. Inhibitors that block the macrodomain could be a new therapeutic strategy for viral suppression. We previously performed a large-scale X-ray crystallography-based fragment screen and discovered a sub-micromolar inhibitor by fragment linking.

Standardization of key performance indicators and metrics for investigational drug services: Consensus recommendations among IDS specialists.

Purpose: There are currently no consensus guidelines on establishing metrics for investigational drug services (IDS). Because of the complexity of research protocols, it remains difficult for sites to track pharmacy productivity and create a baseline for IDS growth within the institution, as well as to perform benchmarking with peer institutions. The goal of this study was to help establish practical guidance for IDS metrics and site utility as applicable.

Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors.

Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest in oncology, both for treating with a single agent and in combination with a KRAS inhibitor. We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.

Mollack: a web server for the automated creation of conformational ensembles for intrinsically disordered proteins.

Unlabelled: Intrinsically disordered proteins (IDPs) play central roles in many biological processes. Consequently, an accurate description of the disordered state is an important step towards a comprehensive understanding of a number of important biological functions. In this work we describe a new web server, Mollack, for the automated construction of unfolded ensembles that uses both experimental and molecular simulation data to construct models for the unfolded state.

Analyzing Ensembles of Amyloid Proteins Using Bayesian Statistics.

Intrinsically disordered proteins (IDPs) are notoriously difficult to study experimentally because they rapidly interconvert between many dissimilar conformations during their biological lifetime, and therefore cannot be described by a single structure. The importance of studying these systems, however, is underscored by the fact that they form toxic aggregates that play a role in the pathogenesis of many disorders. The first step towards a comprehensive understanding of the aggregation mechanism of these proteins involves a description of their thermally accessible states under physiologic conditions.

Brief communication: correcting overestimation when determining two-dimensional occlusal area in human molars.

The robustness index (RI) is determined by multiplying dental mesiodistal and buccolingual diameters, and is used to estimate occlusal area. However, because teeth are not rectangular its calculation consistently causes overestimations. Moreover, teeth, in particular molars, are not identically shaped so overestimations vary.