Computational insights for the discovery of non-ATP competitive inhibitors of MAP kinases.
Due to their role in cellular signaling mitogen activated protein (MAP) kinases represent targets of pharmaceutical interest. However, the majority of known MAP kinase inhibitors compete with cellular ATP and target an ATP binding pocket that is highly conserved in the 500 plus representatives of the human protein kinase family. Here we review progress toward the development of non-ATP competitive MAP kinase inhibitors for the extracellular signal regulated kinases (ERK1/2), the c-jun N-terminal kinases (JNK1/2/3) and the p38 MAPKs (α, β, γ, and δ). Special emphasis is placed on the role of computational methods in the drug discovery process for MAP kinases. Topics include recent advances in X-ray crystallography theory that improve the MAP kinase structures essential to structurebased drug discovery, the use of molecular dynamics to understand the conformational heterogeneity of the activation loop and inhibitors discovered by virtual screening. The impact of an advanced polarizable force field such as AMOEBA used in conjunction with sophisticated kinetic and thermodynamic simulation methods is also discussed.
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA. pren@mail.utexas.edu
Michael J
MJ
Schnieders
Tamer S
TS
Kaoud
Chunli
C
Yan
Kevin N
KN
Dalby
Pengyu
P
Ren
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction
D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D020928:Mitogen-Activated Protein Kinases