Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes

Pharmacol Res. 2016 Jan:103:26-48. doi: 10.1016/j.phrs.2015.10.021. Epub 2015 Oct 31.


Because dysregulation and mutations of protein kinases play causal roles in human disease, this family of enzymes has become one of the most important drug targets over the past two decades. The X-ray crystal structures of 21 of the 27 FDA-approved small molecule inhibitors bound to their target protein kinases are depicted in this paper. The structure of the enzyme-bound antagonist complex is used in the classification of these inhibitors. Type I inhibitors bind to the active protein kinase conformation (DFG-Asp in, αC-helix in). Type I½ inhibitors bind to a DFG-Asp in inactive conformation while Type II inhibitors bind to a DFG-Asp out inactive conformation. Type I, I½, and type II inhibitors occupy part of the adenine binding pocket and form hydrogen bonds with the hinge region connecting the small and large lobes of the enzyme. Type III inhibitors bind next to the ATP-binding pocket and type IV inhibitors do not bind to the ATP or peptide substrate binding sites. Type III and IV inhibitors are allosteric in nature. Type V inhibitors bind to two different regions of the protein kinase domain and are therefore bivalent inhibitors. The type I-V inhibitors are reversible. In contrast, type VI inhibitors bind covalently to their target enzyme. Type I, I½, and II inhibitors are divided into A and B subtypes. The type A inhibitors bind in the front cleft, the back cleft, and near the gatekeeper residue, all of which occur within the region separating the small and large lobes of the protein kinase. The type B inhibitors bind in the front cleft and gate area but do not extend into the back cleft. An analysis of the limited available data indicates that type A inhibitors have a long residence time (minutes to hours) while the type B inhibitors have a short residence time (seconds to minutes). The catalytic spine includes residues from the small and large lobes and interacts with the adenine ring of ATP. Nearly all of the approved protein kinase inhibitors occupy the adenine-binding pocket; thus it is not surprising that these inhibitors interact with nearby catalytic spine (CS) residues. Moreover, a significant number of approved drugs also interact with regulatory spine (RS) residues.

Keywords: ATP-binding site; Afatinib (PubMed CID: 10184653); Catalytic spine; Crizotinib (PubMed CID: 11626560); Erlotinib (PubMed CID: 176870); Gefitinib (PubMed CID: 123631); Imatinib (PubMed CID: 5291); K/E/D/D; Nilotinib (PubMed CID: 644241); Protein kinase structure; Regulatory spine; Residence time; Sorafinib (PubMed CID: 216239); Sunitinib (PubMed CID: 5329102); Tofacitinib (PubMed CID: 9926791); Vemurafenib (PubMed CID: 42611257).

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Molecular Targeted Therapy
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / classification*
  • Protein Kinase Inhibitors / pharmacokinetics


  • Protein Kinase Inhibitors