KIDFamMap: a database of kinase-inhibitor-disease family maps for kinase inhibitor selectivity and binding mechanisms

Abstract

Kinases play central roles in signaling pathways and are promising therapeutic targets for many diseases. Designing selective kinase inhibitors is an emergent and challenging task, because kinases share an evolutionary conserved ATP-binding site. KIDFamMap (http://gemdock.life.nctu.edu.tw/KIDFamMap/) is the first database to explore kinase-inhibitor families (KIFs) and kinase-inhibitor-disease (KID) relationships for kinase inhibitor selectivity and mechanisms. This database includes 1208 KIFs, 962 KIDs, 55 603 kinase-inhibitor interactions (KIIs), 35 788 kinase inhibitors, 399 human protein kinases, 339 diseases and 638 disease allelic variants. Here, a KIF can be defined as follows: (i) the kinases in the KIF with significant sequence similarity, (ii) the inhibitors in the KIF with significant topology similarity and (iii) the KIIs in the KIF with significant interaction similarity. The KIIs within a KIF are often conserved on some consensus KIDFamMap anchors, which represent conserved interactions between the kinase subsites and consensus moieties of their inhibitors. Our experimental results reveal that the members of a KIF often possess similar inhibition profiles. The KIDFamMap anchors can reflect kinase conformations types, kinase functions and kinase inhibitor selectivity. We believe that KIDFamMap provides biological insights into kinase inhibitor selectivity and binding mechanisms.

Figure 1.

Overview of the KIDFamMap database’s process and workflow for identifying KIF and KID relationships using tyrosine-protein kinase ABL1 as the query. (A) Main procedure. (B) Identification of the template candidate ABL1 (PDB code 3CS9) with inhibitor nilotinib of the query using BLASTP to scan the structural template database. The KIDFamMap anchors of ABL1 are shown. (C) Identification of the kinase and compound candidates of the template using BLASTP and compound topology similarity tools, respectively, for the subsequent search of the annotated KII database. The anchors occupied by nilotinib are labeled with red dots. (D) Identification of the kinase-inhibitor candidates with significant interaction similarity (Z-value ≥1.645) of the template ABL1-nilotinib using interaction similarity scores. (E) Identification of the KID relationships of ABL1-nilotinib family. (F) The relationships between KIDFamMap anchors and drug resistance mutations. The anchor NLP1 is formed by three residues (T315, K271 and F382) and the residue T315 forms a hydrogen bond with nilotinib. The mutation, T315I (threonine to isoleucine), reduces inhibitory activity of nilotinib against ABL1 by ∼150 folds (IC₅₀ value from 13 to >2000 nM).

Figure 2.

KIDFamMap search results using compound staurosporine as the query. (A) The query interface for inputting a kinase, compound or disease name. (B) The ‘Template’ page shows summarized query results, related diseases, the available KIFs (such as CKD2-staurosporine and ITK-staurosporine families), kinase conformation types and inhibitor types. (C) The members of the CKD2-staurosporine family (PDB code 1AQ1) share similar interactions and atomic interactions, as seen on the ‘Kinase-Inhibitor Family’ page. KIDFamMap also offers the analysis of family kinases and kinase profiling assays. (D) The ‘Family Anchors’ page provides anchor patterns, interacting residues and moiety preferences of each anchor. (E) The ‘Inhibitor-Anchor Map’ offers the anchor pattern distributions (consensus anchors) of KIIs and the docked poses of family inhibitors. (F) The family related diseases, the associated family kinases and disease allelic variants are provided on the ‘Diseases’ page.

Figure 3.

The anchor patterns and interacting residues of the kinases ABL1, MAPK14, EPHA7 and FES. (A) The partial anchor patterns of the ABL1-nilotinib family. The kinase groups are labeled in parentheses with the corresponding kinase names. (B) The partial anchor patterns of EPHA7 and FES, which are not members of the ABL1-nilotinib family. (C) Residues, pocket surfaces and nilotinib reference poses of ABL1, MAPK14, EPHA7 and FES using the ABL1-nilotinib structure (PDB code 3CS9). (D) Superimposed structures. (E) Residues of ABL1, MAPK14, EPHA7 and FES.

Figure 4.

The correlation between inhibition similarity and interaction similarity (Z-value). Z-values of interaction similarity scores are highly correlated with inhibition similarities and the PCC is 0.97.