3FC1

Crystal structure of p38 kinase bound to pyrimido-pyridazinone inhibitor

Summary for 3FC1

• Entry DOI: 10.2210/pdb3fc1/pdb
• Descriptor: Mitogen-activated protein kinase 14, CHLORIDE ION, 5-(2,6-dichlorophenyl)-2-[(2,4-difluorophenyl)sulfanyl]-6H-pyrimido[1,6-b]pyridazin-6-one, ... (4 entities in total)
• Functional Keywords: kinase inhibitor, atp-binding, nucleotide-binding, nucleus, phosphoprotein, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens
• Cellular location: Cytoplasm (By similarity): Q16539
• Total number of polymer chains: 1
• Total formula weight: 42470.65

Authors

Jacobs, M.D.,Bellon, S. (deposition date: 2008-11-20, release date: 2008-12-09, Last modification date: 2023-12-27)

Primary citation

Pearlman, D.A.
Evaluating the molecular mechanics poisson-boltzmann surface area free energy method using a congeneric series of ligands to p38 MAP kinase.
J.Med.Chem., 48:7796-7807, 2005

PubMed Abstract: The recently described molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method for calculating free energies is applied to a congeneric series of 16 ligands to p38 MAP kinase whose binding constants span approximately 2 orders of magnitude. These compounds have previously been used to test and compare other free energy calculation methods, including thermodynamic integration (TI), OWFEG, ChemScore, PLPScore, and Dock Energy Score. We find that the MM-PBSA performs relatively poorly for this set of ligands, yielding results much inferior to those from TI or OWFEG, inferior to Dock Energy Score, and not appreciably better than ChemScore or PLPScore but at an appreciably larger computational cost than any of these other methods. This suggests that one should be selective in applying the MM-PBSA method and that for systems that are amenable to other free energy approaches, these other approaches may be preferred. We also examine the single simulation approximation for MM-PBSA, whereby the required ligand and protein trajectories are extracted from a single MD simulation rather than two separate MD runs. This assumption, sometimes used to speed the MM-PBSA calculation, is found to yield significantly inferior results with only a moderate net percentage reduction in total simulation time.

PubMed: 16302819
DOI: 10.1021/jm050306m

Experimental method

X-RAY DIFFRACTION (2.4 Å)