Track topics on Twitter Track topics that are important to you
Over the past decade, there has been an increasing interest in covalent inhibition as a drug design strategy. Our own interest in the development of prolyl oligopeptidase (POP) and fibroblast activation protein α (FAP) covalent inhibitors has led us to question whether these two serine proteases were equal in terms of their reactivity towards electrophilic warheads. To streamline such investigations, we exploited both computational and experimental methods to investigate the influence of different reactive groups on both potency and binding kinetics, using both our own series of POP inhibitors and others' discovered hits. A direct correlation between inhibitor reactivity and residence time was demonstrated through quantum mechanics (QM) methods and further supported by experimental studies. This computational method was also successfully applied to FAP, as an overview of known FAP inhibitors confirmed our computational predictions that more reactive warheads (e.g., boronic acids) must be employed to inhibit FAP than for POP.
This article was published in the following journal.
Name: Journal of medicinal chemistry
Covalent inhibitors can obtain optimal selectivity and extended residence time. In this issue of Cell Chemical Biology, Shraga et al. (2019) take a comprehensive computational and experimental approa...
Hypoxia-inducible factor (HIF) stabilizers, also known as inhibitors of HIF prolyl hydroxylase domain (PHD) inhibitors enzymes, are novel small-molecule agents to treat renal anemia. They increase end...
Inhibitors of human p97 (also known as valosin-containing protein) have been actively pursued because of their potential therapeutic applications in cancer and other diseases. However, covalent and ir...
Herein, we describe the development of a novel staple with an electrophilic warhead to enable the generation of stapled peptide covalent inhibitors of the p53-MDM2 protein-protein interaction (PPI). T...
The recognition that only a small percentage of known human gene products are druggable using traditional modes of non-covalent ligand design, has led to a resurgence in targeted covalent inhibitors. ...
The purpose of this study is to evaluate the fetal biophysical profile (BPP) scoring in pregnant women from 20 weeks-0 days' to 36 weeks-6 days' gestation. A biophysical profile (BPP) is a...
Oral supplementation with enzymes that can cut gluten has been suggested as a potential treatment modality for coeliac disease. In the present study the investigators wish to determine if ...
To correlate the HLA type and genetic defect with hemophilia A.
Computational simulation will be performed to represent motion of knees with a dislocating kneecap. Common surgical treatment methods will be simulated and anatomical parameters commonly a...
In this research project the investigators want to figure out whether ultrasound (a non-invasive method) can be used to assess how the fetus is doing during labor.
Compounds that inhibit the action of HYDROXYLASES that act on PROLINE to form HYDROXYPROLINE.
Extracellular protease inhibitors that are secreted from FIBROBLASTS. They form a covalent complex with SERINE PROTEASES and can mediate their cellular internalization and degradation.
A concept, developed in 1983 under the aegis of and supported by the National Library of Medicine under the name of Integrated Academic Information Management Systems, to provide professionals in academic health sciences centers and health sciences institutions with convenient access to an integrated and comprehensive network of knowledge. It addresses a wide cross-section of users from administrators and faculty to students and clinicians and has applications to planning, clinical and managerial decision-making, teaching, and research. It provides access to various types of clinical, management, educational, etc., databases, as well as to research and bibliographic databases. In August 1992 the name was changed from Integrated Academic Information Management Systems to Integrated Advanced Information Management Systems to reflect use beyond the academic milieu.
Analogs of those substrates or compounds which bind naturally at the active sites of proteins, enzymes, antibodies, steroids, or physiological receptors. These analogs form a stable covalent bond at the binding site, thereby acting as inhibitors of the proteins or steroids.
A health care system which combines physicians, hospitals, and other medical services with a health plan to provide the complete spectrum of medical care for its customers. In a fully integrated system, the three key elements - physicians, hospital, and health plan membership - are in balance in terms of matching medical resources with the needs of purchasers and patients. (Coddington et al., Integrated Health Care: Reorganizing the Physician, Hospital and Health Plan Relationship, 1994, p7)
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...
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...