Advertisement

Topics

Allosteric Tuning of Caspase-7: a Fragment-Based Drug Discovery Approach.

08:00 EDT 22nd September 2017 | BioPortfolio

Summary of "Allosteric Tuning of Caspase-7: a Fragment-Based Drug Discovery Approach."

The caspase family of cysteine proteases are highly sought after drug targets due to their essential roles in apoptosis, proliferation and inflammation pathways. High throughput screening efforts to discover inhibitors have gained little traction. Fragment-based screening has emerged as a powerful tool for the discovery of innovative drug leads. This methodology has become a central facet of drug discovery campaigns in the pharmaceutical industry and academia. A fragment-based drug discovery campaign against human caspase-7 resulted in the discovery of a novel series of allosteric inhibitors. An X-ray crystal structure of caspase-7 bound to a fragment hit, and a thorough kinetic characterization of a zymogenic form of the enzyme are used to investigate the allosteric mechanism of inhibition. This work further advances our understanding of the mechanisms of allosteric control of this class of pharmaceutically relevant enzymes, and provides a new path forward for drug discovery efforts.

Affiliation

Journal Details

This article was published in the following journal.

Name: Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Pages:

Links

DeepDyve research library

PubMed Articles [29382 Associated PubMed Articles listed on BioPortfolio]

NMR-Fragment Based Virtual Screening: A Brief Overview.

Fragment-based drug discovery (FBDD) using NMR has become a central approach over the last twenty years for development of small molecule inhibitors against biological macromolecules, to control a var...

Mass spectrometry for fragment screening.

Fragment-based approaches in chemical biology and drug discovery have been widely adopted worldwide in both academia and industry. Fragment hits tend to interact weakly with their targets, necessitati...

Pathway-based technologies for early drug discovery.

Although the traditional drug discovery approach has led to the development of many successful drugs, the attrition rates remain high. Recent advances in systems-oriented approaches (systems-biology a...

Fragment based optimization of metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators in the absence of structural information.

Metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulators (PAMs) have been implicated as potential pharmacotherapy for psychiatric conditions. Screening our corporate compound deck, we...

Binding-Site Compatible Fragment Growing Applied to the Design of β2-Adrenergic Receptor Ligands.

Fragment-based drug discovery is intimately linked to fragment extension approaches that can be accelerated using software for de novo design. Although computers allow for the facile generation of mil...

Clinical Trials [6570 Associated Clinical Trials listed on BioPortfolio]

Characterization of Non-canonical Way in Inflammasome Monocytes of Patients With Severe Sepsis

Activation of caspase-4 and human caspase-5 (orthologs of caspase-11 in mice) in innate immune cells.

Studies of Sulfur Metabolism in Humans

The study test whether the NSAID allosteric site of human sulfotransferase 1A1 (SULT1A1) is operative in humans. The study will test the effects of mefenamic acid (MEF) on the sulfonation ...

Anti-Shiga Toxin Hyperimmune Equine Immunoglobulin F(ab')2 Fragment (INM004) in Healthy Volunteers

This is Prospective Randomized Placebo controlled Single Blind Phase I study to evaluate the safety, tolerance and pharmacokinetics of the anti-Shiga toxin hyperimmune equine immunoglobuli...

Discovery Elbow Multi-Center Prospective Study

The purpose of this prospective clinical trial is to document the performance and clinical outcomes of Biomet Discovery Elbow.

Trial of MitoQ for Raised Liver Enzymes Due to Hepatitis C

A Phase 2, randomized, double-blind, parallel design trial of two doses of mitoquinone mesylate (MitoQ) and of placebo in patients with chronic Hepatitis C. MitoQ is a mitochondria-target...

Medical and Biotech [MESH] Definitions

A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 7; CASPASE 8; and CASPASE 10. Isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.

A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 3 and CASPASE 10. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.

A long pro-domain caspase that contains a caspase recruitment domain in its pro-domain region. Activation of this enzyme can occur via the interaction of its caspase recruitment domain with CARD SIGNALING ADAPTOR PROTEINS. Caspase 2 plays a role in APOPTOSIS by cleaving and activating effector pro-caspases. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.

A long pro-domain caspase that contains a caspase recruitment domain in its pro-domain region. Caspase 9 is activated by pro-apoptotic factors that are released during cell stress and by CARD SIGNALING ADAPTOR PROTEINS. It activates APOPTOSIS by cleaving and activating EFFECTOR CASPASES.

An inhibitor of apoptosis protein that is translated by a rare cap-independent mechanism. It blocks caspase-mediated cellular destruction by inhibiting CASPASE 3; CASPASE 7; and CASPASE 9.

Advertisement
Quick Search
Advertisement
Advertisement

 


DeepDyve research library

Relevant Topics

Drug Discovery
Clinical Approvals Clinical Trials Drug Approvals Drug Delivery Drug Discovery Generics Drugs Prescription Drugs In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are dis...

Pharmacy
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...


Searches Linking to this Article