Bioassay protocol metadata annotation: Proposed standards adoption.

We present a standardized metadata template for assays used in pharmaceutical drug discovery research, according to the FAIR principles. We also describe the use of an automated tool for annotating assays from a variety of sources, including PubChem, commercial assay providers, and the peer-reviewed literature, to this metadata template. Adoption of a standardized metadata template will allow drug discovery scientists to better understand and compare the increasing amounts of assay data becoming available, and will facilitate the use of artificial intelligence tools and other computational methods for analysis and prediction.

Self-reporting data assets and their representation in the pharmaceutical industry.

Standardizing data is crucial for preserving and exchanging scientific information. In particular, recording the context in which data were created ensures that information remains findable, accessible, interoperable, and reusable. Here, we introduce the concept of self-reporting data assets (SRDAs), which preserve data and contextual information.

Coming of age of Allotrope: Proceedings from the Fall 2020 Allotrope Connect.

The Allotrope Foundation (AF) is a group of pharmaceutical, device vendor, and software companies that develops and releases technologies [the Allotrope Data Format (ADF), the Allotrope Foundation Ontology (AFO), and the Allotrope Data Models (ADM)] to simplify the exchange of electronic data. We present here the first comprehensive history of the AF, its structure, a list of members and partners, and an introduction to the technologies. Finally, we provide current insights into the adoption and development of the technologies by summarizing the Fall 2020 Allotrope Connect virtual conference.

Quantifying drug tissue biodistribution by integrating high content screening with deep-learning analysis.

Quantitatively determining in vivo achievable drug concentrations in targeted organs of animal models and subsequent target engagement confirmation is a challenge to drug discovery and translation due to lack of bioassay technologies that can discriminate drug binding with different mechanisms. We have developed a multiplexed and high-throughput method to quantify drug distribution in tissues by integrating high content screening (HCS) with U-Net based deep learning (DL) image analysis models. This technology combination allowed direct visualization and quantification of biologics drug binding in targeted tissues with cellular resolution, thus enabling biologists to objectively determine drug binding kinetics.

Molecular clinical safety intelligence: a system for bridging clinically focused safety knowledge to early-stage drug discovery - the GSK experience.

Drug toxicity is a major cause of late-stage product attrition. During lead identification and optimization phases little information is typically available about which molecules might have safety concerns. A system was built linking chemistry, preclinical and human safety information, enabling scientists to lever safety knowledge across multiple disciplines.

Disclosing ambiguous gene aliases by automatic literature profiling.

Background: Retrieving pertinent information from biological scientific literature requires cutting-edge text mining methods which may be able to recognize the meaning of the very ambiguous names of biological entities. Aliases of a gene share a common vocabulary in their respective collections of PubMed abstracts. This may be true even when these aliases are not associated with the same subset of documents.

Thousands of chemical starting points for antimalarial lead identification.

Malaria is a devastating infection caused by protozoa of the genus Plasmodium. Drug resistance is widespread, no new chemical class of antimalarials has been introduced into clinical practice since 1996 and there is a recent rise of parasite strains with reduced sensitivity to the newest drugs. We screened nearly 2 million compounds in GlaxoSmithKline's chemical library for inhibitors of P.

Functional antagonism of IL-1alpha induced gene expression profiles define the cAMP/PKA pathway as a unique regulator of IL-1alpha signaling networks.

Interleukin-1 (IL-1alpha) induced inflammatory and pro-fibrotic responses in human lung fibroblasts are mediated by activation of MAPK and NFkappaB pathways. The purpose of the present study was to broadly profile the activity of a variety of compounds which function as inhibitors of these key signaling pathways that may affect IL-1alpha mediated gene changes. A reference set of genes was derived from microarray analysis of IL-1alpha stimulated cells.

Thienopyrimidine-based dual EGFR/ErbB-2 inhibitors.

Two new series of potent and selective dual EGFR/ErbB-2 kinase inhibitors derived from novel thienopyrimidine cores have been identified. Isomeric thienopyrimidine cores were evaluated as isosteres for a 4-anilinoquinazoline core and several analogs containing the thieno[3,2-d]pyrimidine core showed anti-proliferative activity with IC(50) values less than 1 microM against human tumor cells in vitro.

6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases.

Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8).

Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram.

Phosphodiesterase catalyzes the hydrolysis of the intracellular second messenger 3',5'-cyclic AMP (cAMP) into the corresponding 5'-nucleotide. Phosphodiesterase 4 (PDE4), the major cAMP-specific PDE in inflammatory and immune cells, is an attractive target for the treatment of asthma and COPD. We have determined crystal structures of the catalytic domain of PDE4B complexed with AMP (2.

Correlation between in vitro peptide binding profiles and cellular activities for estrogen receptor-modulating compounds.

Numerous biochemical and structural studies have shown that the conformation of the estrogen receptor alpha (ERalpha) can be influenced by ligand binding. In turn, the conformational state of ERalpha affects the ability of the receptor to interact with a wide variety of protein accessory factors. To globally investigate ligand-based cofactor recruitment activities of ERalpha, we have applied a flow cytometric multiplexed binding assay to determine the simultaneous binding of ERalpha to over 50 different peptides derived from both known cofactor proteins and random peptide phage display.

Synthesis and SAR of potent EGFR/erbB2 dual inhibitors.

A series of 6-alkoxy-4-anilinoquinazoline compounds was prepared and evaluated for in vitro inhibition of the erbB2 and EGFR kinase activity. The IC(50) values of the best compounds were below 0.10 uM.

Solution structure of the hydroperoxide of Co(III) phleomycin complexed with d(CCAGGCCTGG)2: evidence for binding by partial intercalation.

The bleomycins (BLMs) are natural products that in the presence of iron and oxygen bind to and cause single-strand and double-strand cleavage of DNA. The mode(s) of binding of the FeBLMs that leads to sequence-specific cleavage at pyrimidines 3' to guanines and chemical-specific cleavage at the C-4' H of the deoxyribose of the pyrimidine has remained controversial. 2D NMR studies using the hydroperoxide of CoBLM (HOO-CoBLM) have demonstrated that its bithiazole tail binds by partial intercalation to duplex DNA.