Journal of Chemical Information and Modeling | VOL. 62
Read

KiSSim: Predicting Off-Targets from Structural Similarities in the Kinome

Publication Date May 10, 2022

Abstract

Protein kinases are among the most important drug targets because their dysregulation can cause cancer, inflammatory and degenerative diseases, and many more. Developing selective inhibitors is challenging due to the highly conserved binding sites across the roughly 500 human kinases. Thus, detecting subtle similarities on a structural level can help explain and predict off-targets among the kinase family. Here, we present the kinase-focused, subpocket-enhanced KiSSim fingerprint (Kinase Structural Similarity). The fingerprint builds on the KLIFS pocket definition, composed of 85 residues aligned across all available protein kinase structures, which enables residue-by-residue comparison without a computationally expensive alignment. The residues' physicochemical and spatial properties are encoded within their structural context including key subpockets at the hinge region, the DFG motif, and the front pocket. Since structure was found to contain information complementary to sequence, we used the fingerprint to calculate all-against-all similarities within the structurally covered kinome. We could identify off-targets that are unexpected if solely considering the sequence-based kinome tree grouping; for example, Erlobinib's known kinase off-targets SLK and LOK show high similarities to the key target EGFR (TK group), although belonging to the STE group. KiSSim reflects profiling data better or at least as well as other approaches such as KLIFS pocket sequence identity, KLIFS interaction fingerprints (IFPs), or SiteAlign. To r...

Concepts
Powered ByUnsilo

Open-source Python Package
TK Group
Front Pocket
DFG Motif
Interaction Fingerprints
Important Drug Targets
Feature Resolution
Hinge Region
Spatial Properties
Kinase Family

Introducing Weekly Round-ups!Beta

Powered by R DiscoveryR Discovery

Round-ups are the summaries of handpicked papers around trending topics published every week. These would enable you to scan through a collection of papers and decide if the paper is relevant to you before actually investing time into reading it.

Climate change Research Articles published between Jun 20, 2022 to Jun 26, 2022

R DiscoveryJun 27, 2022
R DiscoveryArticles Included:  2

One eighth of the bird species in the world is considered globally threatened; the avifauna of Iraq comprises 409 species and is considered as the maj...

Read More

Coronavirus Pandemic

You can also read COVID related content on R COVID-19

R ProductsCOVID-19

ONE PROBLEM . ONE PURPOSE . ONE PLACE

Creating the world’s largest AI-driven & human-curated collection of research, news, expert recommendations and educational resources on COVID-19

COVID-19 Dashboard