Discovery and development strategies for SARS-CoV-2 NSP3 macrodomain inhibitors

The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibiotic compound aztreonam, to the active site of the macrodomain provide valuable structure–activity relationship information that support current approaches and open up new avenues for NSP3 macrodomain inhibitor development

Selective inhibition of the K⁺ efflux sensitive NLRP3 pathway by Cl^- channel modulation.

From Europe PMC via Jisc Publications RouterHistory: ppub 2020-10-01, epub 2020-10-12Publication status: PublishedFunder: Medical Research Council; Grant(s): MR/N029992/1, MC_PC_17172, MR/T016515/1Funder: Alzheimer's Society; Grant(s): AS-PhD-16-002, 10Funder: Alzheimers Research UK; Grant(s): ARUK-2015DDI-OXThe NLRP3 inflammasome regulates production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and contributes to inflammation exacerbating disease. Fenamate non-steroidal anti-inflammatory drugs (NSAIDs) were recently described as NLRP3 inflammasome inhibitors via chloride channel inhibition. Fenamate NSAIDs inhibit cyclooxygenase (COX) enzymes, limiting their potential as therapeutics for NLRP3-associated diseases due to established side effects. The aim here was to develop properties of the fenamates that inhibit NLRP3, and at the same time to reduce COX inhibition. We synthesised a library of analogues, with feedback from in silico COX docking potential, and IL-1β release inhibitory activity. Through iterative screening and rational chemical design, we established a collection of chloride channel inhibiting active lead molecules with potent activity at the canonical NLRP3 inflammasome and no activity at COX enzymes, but only in response to stimuli that activated NLRP3 by a K+ efflux-dependent mechanism. This study identifies a model for the isolation and removal of unwanted off-target effects, with the enhancement of desired activity, and establishes a new chemical motif for the further development of NLRP3 inflammasome inhibitors

Computational Chemistry on a Budget: Supporting Drug Discovery with Limited Resources.

An increasing number of new drugs have their origin in small biotech or academia. In contrast to big pharma, these environments are often more limited in terms of resources, and this necessitates different approaches to the drug discovery process. In this review, we outline how computational methods can help advance drug discovery in a setting with more limited resources and we share what, based on our experience, are the best practices for these methods

TargetDB: A target information aggregation tool and tractability predictor.

When trying to identify new potential therapeutic protein targets, access to data and knowledge is increasingly important. In a field where new resources and data sources become available every day, it is crucial to be able to take a step back and look at the wider picture in order to identify potential drug targets. While this task is routinely performed by bespoke literature searches, it is often time-consuming and lacks uniformity when comparing multiple targets at one time. To address this challenge, we developed TargetDB, a tool that aggregates public information available on given target(s) (links to disease, safety, 3D structures, ligandability, novelty, etc.) and assembles it in an easy to read output ready for the researcher to analyze. In addition, we developed a target scoring system based on the desirable attributes of good therapeutic targets and machine learning classification system to categorize novel targets as having promising or challenging tractrability. In this manuscript, we present the methodology used to develop TargetDB as well as test cases

Selective inhibition of the K

From PubMed via Jisc Publications RouterPublication status: epublishThe NLRP3 inflammasome regulates production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and contributes to inflammation exacerbating disease. Fenamate non-steroidal anti-inflammatory drugs (NSAIDs) were recently described as NLRP3 inflammasome inhibitors chloride channel inhibition. Fenamate NSAIDs inhibit cyclooxygenase (COX) enzymes, limiting their potential as therapeutics for NLRP3-associated diseases due to established side effects. The aim here was to develop properties of the fenamates that inhibit NLRP3, and at the same time to reduce COX inhibition. We synthesised a library of analogues, with feedback from COX docking potential, and IL-1β release inhibitory activity. Through iterative screening and rational chemical design, we established a collection of chloride channel inhibiting active lead molecules with potent activity at the canonical NLRP3 inflammasome and no activity at COX enzymes, but only in response to stimuli that activated NLRP3 by a K efflux-dependent mechanism. This study identifies a model for the isolation and removal of unwanted off-target effects, with the enhancement of desired activity, and establishes a new chemical motif for the further development of NLRP3 inflammasome inhibitors. [Abstract copyright: This journal is © The Royal Society of Chemistry.

A genetics-led approach defines the drug target landscape of 30 immune-related traits

ISSN:1061-4036ISSN:1546-171