KLIFS: A Knowledge-Based Structural Database To Navigate Kinase–Ligand Interaction Space

Linden, Oscar P.J. van; Kooistra, Albert J.; Leurs, Rob; Esch, Iwan J. P. de; Graaf, Chris de

doi:10.1021/jm400378w

Cited by 254 publications

(342 citation statements)

References 135 publications

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“…Among the 518 kinases, it has been estimated that about 190 unique human kinase structures have been solved encompassing over 1,200 individual kinase ligand co-complex structures [ 10 ]. These numbers agree with a similar annotated and aligned database maintained internally at Eli Lilly [ 11 ].…”

Section: Kinase X-ray Structuressupporting

confidence: 67%

“…In fact, ~200 of the unique ligands bound to kinases in the PDB could be considered fragments (< =18 heavy atoms) in our annotated database. The numbers are a little higher than those found in an internal analysis of the KLIFs database [ 10 ] that showed ~1,000 unique ligand structures and approximately 100 fragments. The KLIFS database, however, does not include non-protein kinases or kinases with non-kinase domains.…”

Section: Kinase X-ray Structuresmentioning

confidence: 54%

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Fragment-Based Design of Kinase Inhibitors: A Practical Guide

Erickson

2015

Methods in Molecular Biology

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Fragment-based drug design has become an important strategy for drug design and development over the last decade. It has been used with particular success in the development of kinase inhibitors, which are one of the most widely explored classes of drug targets today. The application of fragment-based methods to discovering and optimizing kinase inhibitors can be a complicated and daunting task; however, a general process has emerged that has been highly fruitful. Here a practical outline of the fragment process used in kinase inhibitor design and development is laid out with specific examples. A guide to the overall process from initial discovery through fragment screening, including the difficulties in detection, to the computational methods available for use in optimization of the discovered fragments is reported.

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Section: Kinase X-ray Structuressupporting

confidence: 67%

Section: Kinase X-ray Structuresmentioning

confidence: 54%

Fragment-Based Design of Kinase Inhibitors: A Practical Guide

Erickson

2015

Methods in Molecular Biology

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“…The ligand binding site residues of 85 kinases are aligned and included in the kinase-ligand interaction fingerprints and structure (KLIFS) database [44]. KLIFS can conveniently identify family specific interaction features and classify ligands based on their binding modes.…”

Section: Klifsmentioning

confidence: 99%

“…1252 Aligned human kinase-ligand cocrystal complexes from PDB database have been adopted to construct KLIFS [45]. Furthermore, different kinase-ligand interactions were featured by molecular interaction fingerprints [44]. 1100 Cocrystal ligands extracted from KLIFS were used (http://www.vu-compmedchem.nl).…”

Section: Klifsmentioning

confidence: 99%

Fragment virtual screening based on Bayesian categorization for discovering novel VEGFR-2 scaffolds

et al. 2015

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The discovery of novel scaffolds against a specific target has long been one of the most significant but challengeable goals in discovering lead compounds. A scaffold that binds in important regions of the active pocket is more favorable as a starting point because scaffolds generally possess greater optimization possibilities. However, due to the lack of sufficient chemical space diversity of the databases and the ineffectiveness of the screening methods, it still remains a great challenge to discover novel active scaffolds. Since the strengths and weaknesses of both fragment-based drug design and traditional virtual screening (VS), we proposed a fragment VS concept based on Bayesian categorization for the discovery of novel scaffolds. This work investigated the proposal through an application on VEGFR-2 target. Firstly, scaffold and structural diversity of chemical space for 10 compound databases were explicitly evaluated. Simultaneously, a robust Bayesian classification model was constructed for screening not only compound databases but also their corresponding fragment databases. Although analysis of the scaffold diversity demonstrated a very unevenly distribution of scaffolds over molecules, results showed that our Bayesian model behaved better in screening fragments than molecules. Through a literature retrospective research, several generated fragments with relatively high Bayesian scores indeed exhibit VEGFR-2 biological activity, which strongly proved the effectiveness of fragment VS based on Bayesian categorization models. This investigation of Bayesian-based fragment VS can further emphasize the necessity for enrichment of compound databases employed in lead discovery by amplifying the diversity of databases with novel structures.

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“…[16,17] The last key pocket is placed in front of the AS and below the aC-helix. For this reason,w e refer to this pocket as the aC-helix pocket (aCh-P), [9] which is formed by Arg67, Arg70, andG lu71 side chains.…”

Section: Introductionmentioning

confidence: 99%

A Comprehensive Structural Overview of p38α Mitogen‐Activated Protein Kinase in Complex with ATP‐Site and Non‐ATP‐Site Binders

et al. 2017

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Herein we review all the currently available ATP‐site and non‐ATP‐site ligands bound to p38α mitogen‐activated protein kinase (MAPK) available in the RCSB Protein Data Bank (PDB). The co‐crystallized inhibitors have been classified into different families according to their experimental binding mode and chemical structure, and the ligand–protein interactions are discussed using the most representative compounds. This systematic structural analysis could provide some take‐home lessons for drug discovery programs aimed at the rational identification and optimization of new p38α MAPK inhibitors.

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KLIFS: A Knowledge-Based Structural Database To Navigate Kinase–Ligand Interaction Space

Cited by 254 publications

References 135 publications

Fragment-Based Design of Kinase Inhibitors: A Practical Guide

Fragment-Based Design of Kinase Inhibitors: A Practical Guide

Fragment virtual screening based on Bayesian categorization for discovering novel VEGFR-2 scaffolds

A Comprehensive Structural Overview of p38α Mitogen‐Activated Protein Kinase in Complex with ATP‐Site and Non‐ATP‐Site Binders

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