KLIFS: an overhaul after the first 5 years of supporting kinase research

Abstract

Kinases are a prime target of drug development efforts with >60 drug approvals in the past two decades. Due to the research into this protein family, a wealth of data has been accumulated that keeps on growing. KLIFS-Kinase-Ligand Interaction Fingerprints and Structures-is a structural database focusing on how kinase inhibitors interact with their targets. The aim of KLIFS is to support (structure-based) kinase research through the systematic collection, annotation, and processing of kinase structures. Now, 5 years after releasing the initial KLIFS website, the database has undergone a complete overhaul with a new website, new logo, and new functionalities. In this article, we start by looking back at how KLIFS has been used by the research community, followed by a description of the renewed KLIFS, and conclude with showcasing the functionalities of KLIFS. Major changes include the integration of approved drugs and inhibitors in clinical trials, extension of the coverage to atypical kinases, and a RESTful API for programmatic access. KLIFS is available at the new domain https://klifs.net.

Figure 1.

An overview of the pipeline and contents of KLIFS. (A) The left kinome shows the current structural coverage of KLIFS for each kinase. The size of the circles indicates the number of structures for each kinase with in purple the newly covered kinases, in red the current status of previously covered kinases with in yellow on top the status at the time of the previous publication (4). The right kinome shows the ligand coverage based on ChEMBL and is colored according to the % of ligands that are analogs of the inhibitors present in KLIFS. Of note, the circles represent the number of structures and ligands on a logarithmic scale. The kinome visualizations were created using KinMap (44). (B) A schematic depiction of the pipeline of how the structures are processed before their annotation, calculation, curation and presentation in KLIFS.

Figure 2.

(A) Partial reconstruction of Ponatinib using fragments from structures released before 2009. Fragments from Imatinib, Nilotinib and HET-code 4RB are shown together on top of the binding mode of ponatinib within the kinase binding site. (B) Partial reconstruction of Erdafitinib based on fragments from structures released before 2016. Fragments from PD173074 and NVP-BSK805 are shown on top of the binding mode of Erdafinitib within the kinase binding site. (C) An analog search for the recently approved inhibitor Capmatinib identified HET-code 6XE as the most similar inhibitor in KLIFS with a fingerprint similarity of 0.54 (Tanimoto score using the Morgan fingerprint). (D) An overlay of a structure with a hit from an ultra-small fragment screen with a substructure search hit within KLIFS. This overlay shows a conservation of the binding pose of the hinge-binding fragment in 6QA1 with the larger ligand with this fragment as substructure as observed in 1W7H.