Related Experiment Video

Updated: May 13, 2025

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
10:58

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules

Published on: July 25, 2013

17.0K

Design, Synthesis, and Biological Implications of Autotaxin inhibitors with a Three-Point lock binding mode

Nicolas Desroy1, Razvan Borza2, Jörg Heiermann3

  • 1Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.

Bioorganic & Medicinal Chemistry
|April 15, 2025
PubMed

Insights

New autotaxin (ATX) inhibitors, termed type VI, target the enzyme

Area of Science:

  • Biochemistry
  • Enzymology
  • Medicinal Chemistry

Background:

  • Autotaxin (ATX) is a key enzyme in lysophosphatidic acid (LPA) signaling.
  • ATX/LPA signaling is implicated in diseases like fibrosis and cancer.
  • Existing ATX inhibitors (Types I-V) target specific parts of the enzyme's tripartite site.

Purpose of the Study:

  • To explore a novel class of ATX inhibitors targeting the active site, pocket, and tunnel simultaneously.
  • To design and synthesize new ATX inhibitors based on the type IV compound GLPG1690.

Main Methods:

  • Design and synthesis of novel ATX inhibitor analogs.
  • Co-crystallization studies to elucidate binding modes.
  • In vitro enzymatic assays to determine inhibitory activity.
  • Cellular and phenotypic assays to assess compound efficacy.

Main Results:

  • Novel
  • Type VI inhibitors, compounds 4 and 41, demonstrated significantly enhanced inhibitory activity (approximately 40-fold) compared to a close type IV analog.
  • Type VI inhibitors exhibited comparable cellular and phenotypic activity to the type IV inhibitor GLPG1690.

Conclusions:

  • Identification of a new
  • The discovery of type VI inhibitors provides a new binding mode for ATX inhibitor design.
  • Further research is warranted to evaluate the therapeutic potential of these novel inhibitors.
Keywords:
AutotaxinAutotaxin inhibitorCrystal structureImidazo[12–b]pyridazineLysophosphatidic acidZinc binder

More Related Videos

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

11.2K
Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions08:31

Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions

Published on: December 1, 2020

4.9K

Related Concept Videos

Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.6K
Ligand Binding and Linkage00:49

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.7K
Targets for Drug Action: Overview01:26

Targets for Drug Action: Overview

Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
5.9K
ATP Synthase: Mechanism01:48

ATP Synthase: Mechanism

In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
13.7K
Ligand Binding Sites02:40

Ligand Binding Sites

Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
12.6K
Enzyme Inhibition01:30

Enzyme Inhibition

Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
77.5K