Rational design and combinatorial evaluation of enzyme inhibitor scaffolds: identification of novel inhibitors of matrix metalloproteinases

Journal of Medicinal Chemistry
A K SzardeningsD A Campbell

Abstract

The discovery of a novel series of heterocyclic matrix metalloproteinase (MMPs) inhibitors is described. Published crystal structures of peptidyl hydroxamates bound to MMPs were the basis for the rational design of diketopiperazine (DKP) inhibitors. Combinatorial libraries were prepared and evaluated for their ability to inhibit collagenase-1, stromelysin-1, and gelatinase-B substrate hydrolysis. Deconvolution of active pools resulted in the identification of potent inhibitors (IC50's < 100 nM) of collagenase-1 and gelatinase-B, with the most potent inhibitor exhibiting an IC50 of 30 nM against collagenase-1. A description of the combinatorial evaluation process, as well as initial SAR interpretation for this novel series, is provided.

Citations

Jun 27, 2007·Chembiochem : a European Journal of Chemical Biology·Dustin J MalyJonathan A Ellman
Apr 2, 2003·Bioorganic & Medicinal Chemistry Letters·Imre SchlemmingerChristopher J Schofield
May 29, 2000·Current Opinion in Chemical Biology·C Barnes, S Balasubramanian
Jul 25, 2009·Accounts of Chemical Research·Ralph F HirschmannAmos B Smith
Aug 2, 2008·Chemical & Pharmaceutical Bulletin·Satoshi Ichikawa
Jun 18, 2002·Pharmacotherapy·Michelle A RudekWilliam D Figg
Jul 27, 1999·Protein Expression and Purification·N RoyG Das
Feb 1, 2017·Chemical Biology & Drug Design·Balmukund Sureshkumar ThakkarRichard Alan Engh
Jan 2, 2007·Journal of Inorganic Biochemistry·Timothy W Failes, Trevor W Hambley
May 13, 2009·Journal of Chemical Information and Modeling·Hongming ChenTim Lange
Dec 26, 2001·Chemical Reviews·M WhittakerA J Gearing
Jan 10, 2002·Chemical Reviews·Viktor Krchnák, Mark W Holladay
Apr 5, 2000·Journal of Combinatorial Chemistry·R E Dolle, K H Nelson
Jan 10, 2001·Journal of Combinatorial Chemistry·S TopiolJ R Wareing
Nov 14, 2006·Journal of Combinatorial Chemistry·Marcus TullbergMorten Grøtli
Oct 3, 1999·Journal of Medicinal Chemistry·R A HoughtenJ M Ostresh

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.