Assessment of the putative binding conformation of a pyrazolopyridine class of inhibitors of MAPKAPK2 using computational studies.
The Ser/Thr protein kinase MAPKAP kinase2 (MAPKAPK2 or MK2) plays an important role in inflammation. A comparison of several crystal structures of MK2 shows that differences in active and inactive conformations result in large part from structural variations within the conformations of the glycine rich loop (p-loop) regions. We propose the most preferred binding conformation of two classes of MK2 inhibitors and suggest plausible critical interactions with active site residues. The predicted binding conformations of the two classes of MK2 inhibitors depend upon their orientation in the active site and activities were well correlated with the sum of D and G scores. A qualitative relationship between the sum of D and G scores and the measured activities can be demonstrated.
Miglani
Rajni
R
Division of Molecular Modeling, New Drug Discovery Research, Ranbaxy Laboratories Limited, Sector-18, Gurgaon-122001, India. rajni.miglani@gmail.com
Cliffe
Ian A
IA
Voleti
Sreedhara R
SR
D000255:Adenosine Triphosphate / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D003198:Computer Simulation; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D005998:Glycine; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D015203:Reproducibility of Results; D000099190:MAP-Kinase-Activated Kinase 2
D000255:Adenosine Triphosphate; D005998:Glycine; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011725:Pyridines; D000099190:MAP-Kinase-Activated Kinase 2; C118531:pyrazolopyridine