A Comprehensive Structural Overview of p38α MAPK in Complex with Type I Inhibitors

Abstract

p38α mitogen-activated protein kinase (MAPK) is a well-recognized therapeutic target for the treatment of autoimmune and inflammatory diseases. Over the past two decades, tremendous efforts have been focused on the discovery and development of small-molecule p38α MAPK inhibitors, although currently no drugs targeting this protein are clinically available. Therefore, the identification of novel chemotypes that are able to inhibit p38α MAPK function is still of great therapeutic significance. With the objective to support drug discovery programs aimed at identifying new immunomodulators acting on p38α MAPK, herein we present a complete overview of the available crystal structures of this protein in complex with ATP-site type I inhibitors. The 85 available complexes are classified by chemotype and experimental binding mode, and the ligand-protein interactions are discussed using the most representative inhibitors. The type and frequency of key inhibitor features are analyzed to give a final summary of the chemical requirements of promising p38α MAPK inhibitors. The proposed pharmacophore can be exploited to enhance the opportunities to identify novel type I inhibitors of p38α MAPK.

Estimation of relative free energies of binding using pre‐computed ensembles based on the single‐step free energy perturbation and the site‐identification by Ligand competitive saturation approaches

“…The initial protein coordinates for all the FEP and SSFEP simulations were obtained from PDB crystal structures 3EQR and 4EHW for ACK1 (see specific ligands in the following paragraph), with 3EQR used to initiate the SILCS simulations. With p38 MAP kinase 3FLY and 3D7Z were used for the FEP and SSFEP simulations with 3FLY used for the SILCS simulations.…”

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

“…[8,17,[20][21][22][23] Eighty-five such structures were already described in our previous review [18] focusedo nT I-Is, and thus will be not discussed herein. The remaining PDB complexes are initially clustered according to the type (e.g.,T I-Is) and then the chemotype of the boundinhibitor ( Table 2).…”

“…[18] Figure 5. Examples of A) Gly-flip (e.g., 33,5TCO) and B) Leu-Flip (e.g., 38, 4KIN) hinge conformation.…”

“…The first crystal structure of human p38a MAPK was made publicly availablei n1 996 by Wilson et al [30] Since then, 247 crystal structures of this kinase have been deposited in the PDB, 174 of which showh uman wild-type p38a MAPK with bound inhibitors classified as ATP-site and non-ATP-site binders (Figures 2a nd 3). [8,17,[20][21][22][23] Eighty-five such structures were already described in our previous review [18] focusedo nT I-Is, and thus will be not discussed herein. The remaining PDB complexes are initially clustered according to the type (e.g.,T I-Is) and then the chemotype of the boundinhibitor ( Table 2).…”

“…[8] In 2015 we reported an in-depths tructurala nalysiso fT I-Is boundt op 38a MAPK. [18] Now,b yu sing the same methodological approach as in our previous paper,w eh ave extended the analysist oc over all PDB-deposited crystal structures of ligands in complex with p38a MAPK. Indeed, while efficacy,s electivity, active site conformationc hanges,a nd structure-activity relationships have been widelyd escribed for individual p38a MAPK inhibitors, [1,17,[26][27][28][29] to the best of our knowledge ac omprehensive structural overview of ligand binding and structural features for all types of bindershas been missing.…”