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Related Concept Videos

Conserved Binding Sites01:49

Conserved Binding Sites

Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
Protein-protein Interfaces02:04

Protein-protein Interfaces

Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a polypeptide...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
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...
Protein Networks02:26

Protein Networks

An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...

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Related Experiment Video

Updated: May 28, 2026

Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
08:49

Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis

Published on: June 20, 2025

Structure-Based Identification of JAK1-Selective Candidates Using Ensemble Docking and Interaction Analysis.

Nicoleta Stoian1, Sorin Avram1, Liliana Halip1

  • 1Department of Computational Chemistry, "Coriolan Drăgulescu" Institute of Chemistry Timișoara, Romanian Academy, 24 Mihai Viteazu Avenue, 300223 Timișoara, Romania.

Pharmaceuticals (Basel, Switzerland)
|May 27, 2026
PubMed
Summary

Developing selective JAK1 inhibitors is challenging due to structural similarities within the JAK family. This study presents a computational framework to identify JAK1-biased drug scaffolds, prioritizing compounds with preferential JAK1 recognition.

Keywords:
JAK1 inhibitorsautoimmune diseaseskinase fingerprintingmolecular dockingscaffold analysisselectivitystructure-based drug design

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Last Updated: May 28, 2026

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08:49

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Published on: June 20, 2025

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

Area of Science:

  • Biochemistry
  • Computational Chemistry
  • Drug Discovery

Background:

  • Selective inhibition of Janus Kinase 1 (JAK1) is crucial for cytokine-signaling therapeutics but hindered by the structural similarity of the JAK family.
  • Identifying JAK1-selective compounds requires understanding the structural determinants of kinase inhibition and isoform discrimination.

Purpose of the Study:

  • To develop and validate an integrated computational framework for elucidating JAK1 selectivity.
  • To prioritize drug-like compounds with predicted JAK1 preference using advanced modeling techniques.

Main Methods:

  • Utilized large-scale binding-site conformational analysis and ensemble docking of JAK1 and JAK2 structures.
  • Employed protein-ligand interaction fingerprinting (PLIF) to analyze binding modes and identify selectivity features.
  • Validated docking performance and applied the workflow to screen a library of ~6000 compounds.

Main Results:

  • The computational framework achieved high accuracy (AUC = 0.78-0.82) in distinguishing active from inactive ligands.
  • Identified a conserved hinge-binding motif for potency and a JAK1-specific hotspot contributing to isoform discrimination.
  • Prioritized 174 drug-like compounds predicted to have preferential JAK1 recognition and reduced JAK2 engagement.

Conclusions:

  • Defined key structural and physicochemical features essential for JAK1 selectivity.
  • Demonstrated the utility of ensemble-based modeling in guiding the discovery of selective kinase inhibitors.