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Theoretical and experimental design of atypical kinase inhibitors: application to p38 MAP kinase.

McClure KF, Abramov YA, Laird ER, Barberia JT, Cai W, Carty TJ, Cortina SR, Danley DE, Dipesa AJ, Donahue KM, Dombroski MA, Elliott NC, Gabel CA, Han S, Hynes TR, Lemotte PK, Mansour MN, Marr ES, Letavic MA, Pandit J, Ripin DB, Sweeney FJ, Tan D, Tao Y
J Med Chem 48 5728-37 (2005)
Cited: 24 times
EuropePMC logo PMID: 16134941

Abstract

Mimics of the benzimidazolone nucleus found in inhibitors of p38 kinase are proposed, and their theoretical potential as bioisosteres is described. A set of calculated descriptors relevant to the anticipated binding interaction for the fragments 1-methyl-1H-benzotriazole 5, 3-methyl-benzo[d]isoxazole 3, and 3-methyl-[1,2,4]triazolo[4,3-a]pyridine 4, pyridine 1, and 1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one 2 are reported. The design considerations and synthesis of p38 inhibitors based on these H-bond acceptor fragments is detailed. Comparative evaluation of the pyridine-, benzimidazolone-, benzotriazole-, and triazolopyridine-based inhibitors shows the triazoles 20 and 25 to be significantly more potent experimentally than the benzimidazolone after which they were modeled. An X-ray crystal structure of 25 bound to the active site shows that the triazole group serves as the H-bond acceptor but unexpectedly as a dual acceptor, inducing movement of the crossover connection of p38alpha. The computed descriptors for the hydrophobic and pi-pi interaction capacities were the most useful in ranking potency.

Articles - 1zzl mentioned but not cited (6)

  1. An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics. Armen RS, Chen J, Brooks CL. J Chem Theory Comput 5 2909-2923 (2009)
  2. Protein kinase-inhibitor database: structural variability of and inhibitor interactions with the protein kinase P-loop. Patel RY, Doerksen RJ. J Proteome Res 9 4433-4442 (2010)
  3. Trilobatin Protects Against Aβ25-35-Induced Hippocampal HT22 Cells Apoptosis Through Mediating ROS/p38/Caspase 3-Dependent Pathway. Chen N, Wang J, He Y, Xu Y, Zhang Y, Gong Q, Yu C, Gao J. Front Pharmacol 11 584 (2020)
  4. p38α Mitogen-Activated Protein Kinase Is a Druggable Target in Pancreatic Adenocarcinoma. Yang L, Sun X, Ye Y, Lu Y, Zuo J, Liu W, Elcock A, Zhu S. Front Oncol 9 1294 (2019)
  5. Towards good correlation between fragment molecular orbital interaction energies and experimental IC50 for ligand binding: A case study of p38 MAP kinase. Sheng Y, Watanabe H, Maruyama K, Watanabe C, Okiyama Y, Honma T, Fukuzawa K, Tanaka S. Comput Struct Biotechnol J 16 421-434 (2018)
  6. Anhedonic- and anxiogenic-like behaviors and neurochemical alterations are abolished by a single administration of a selenium-containing compound in chronically stressed mice. Casaril AM, Lourenço DA, Domingues M, Smaniotto TÂ, Birmann PT, Vieira B, Sonego MS, Seixas FK, Collares T, Lenardão EJ, Savegnago L. Compr Psychoneuroendocrinol 6 100054 (2021)


Reviews citing this publication (2)

  1. p38 MAPK inhibitors: a patent review (2012 - 2013). Bühler S, Laufer SA. Expert Opin Ther Pat 24 535-554 (2014)
  2. A Comprehensive Structural Overview of p38α MAPK in Complex with Type I Inhibitors. Astolfi A, Iraci N, Manfroni G, Barreca ML, Cecchetti V. ChemMedChem 10 957-969 (2015)

Articles citing this publication (16)

  1. Synopsis of some recent tactical application of bioisosteres in drug design. Meanwell NA. J Med Chem 54 2529-2591 (2011)
  2. Drug discovery for human African trypanosomiasis: identification of novel scaffolds by the newly developed HTS SYBR Green assay for Trypanosoma brucei. Faria J, Moraes CB, Song R, Pascoalino BS, Lee N, Siqueira-Neto JL, Cruz DJ, Parkinson T, Ioset JR, Cordeiro-da-Silva A, Freitas-Junior LH. J Biomol Screen 20 70-81 (2015)
  3. Virtual screening using a conformationally flexible target protein: models for ligand binding to p38α MAPK. Vinh NB, Simpson JS, Scammells PJ, Chalmers DK. J Comput Aided Mol Des 26 409-423 (2012)
  4. Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception. Syeda SS, Sánchez G, Hong KH, Hawkinson JE, Georg GI, Blanco G. J Med Chem 61 1800-1820 (2018)
  5. Palladium-catalyzed coupling of aldehyde-derived hydrazones: practical synthesis of triazolopyridines and related heterocycles. Thiel OR, Achmatowicz MM, Reichelt A, Larsen RD. Angew Chem Int Ed Engl 49 8395-8398 (2010)
  6. Preclinical pharmacokinetics and metabolism of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3-a]pyridine, a novel and selective p38alpha inhibitor: identification of an active metabolite in preclinical species and human liver microsomes. Kalgutkar AS, Hatch HL, Kosea F, Nguyen HT, Choo EF, McClure KF, Taylor TJ, Henne KR, Kuperman AV, Dombroski MA, Letavic MA. Biopharm Drug Dispos 27 371-386 (2006)
  7. The design and synthesis of novel alpha-ketoamide-based p38 MAP kinase inhibitors. Montalban AG, Boman E, Chang CD, Ceide SC, Dahl R, Dalesandro D, Delaet NG, Erb E, Ernst JT, Gibbs A, Kahl J, Kessler L, Lundström J, Miller S, Nakanishi H, Roberts E, Saiah E, Sullivan R, Wang Z, Larson CJ. Bioorg Med Chem Lett 18 1772-1777 (2008)
  8. Structure-activity relationships of triazolopyridine oxazole p38 inhibitors: identification of candidates for clinical development. McClure KF, Letavic MA, Kalgutkar AS, Gabel CA, Audoly L, Barberia JT, Braganza JF, Carter D, Carty TJ, Cortina SR, Dombroski MA, Donahue KM, Elliott NC, Gibbons CP, Jordan CK, Kuperman AV, Labasi JM, Laliberte RE, McCoy JM, Naiman BM, Nelson KL, Nguyen HT, Peese KM, Sweeney FJ, Taylor TJ, Trebino CE, Abramov YA, Laird ER, Volberg WA, Zhou J, Bach J, Lombardo F. Bioorg Med Chem Lett 16 4339-4344 (2006)
  9. Synthesis, p38α MAP kinase inhibition, anti-inflammatory activity, and molecular docking studies of 1,2,4-triazole-based benzothiazole-2-amines. Tariq S, Alam O, Amir M. Arch Pharm (Weinheim) 351 e1700304 (2018)
  10. Structural effects on the phosphorylation of 3-substituted 1-beta-D-ribofuranosyl-1,2,4-triazoles by human adenosine kinase. Kumarapperuma SC, Sun Y, Jeselnik M, Chung K, Parker WB, Jonsson CB, Arterburn JB. Bioorg Med Chem Lett 17 3203-3207 (2007)
  11. Continued exploration of the triazolopyridine scaffold as a platform for p38 MAP kinase inhibition. Jerome KD, Rucker PV, Xing L, Shieh HS, Baldus JE, Selness SR, Letavic MA, Braganza JF, McClure KF. Bioorg Med Chem Lett 20 469-473 (2010)
  12. A Greener and Efficient Method for Nucleophilic Aromatic Substitution of Nitrogen-Containing Fused Heterocycles. Campos JF, Loubidi M, Scherrmann MC, Berteina-Raboin S. Molecules 23 E684 (2018)
  13. Facile route for N 1-aryl benzotriazoles from diazoamino arynes via CuI-mediated intramolecular N-arylation. Kale RR, Prasad V, Hussain HA, Tiwari VK. Tetrahedron Lett 51 5740-5743 (2010)
  14. Prediction of the binding affinity of compounds with diverse scaffolds by MP-CAFEE. Okada O, Yamashita H, Takedomi K, Ono S, Sunada S, Kubodera H. Biophys Chem 180-181 119-126 (2013)
  15. Synthesis of 1,2,4-Triazolo[4,3-a]pyridines and Related Heterocycles by Sequential Condensation and Iodine-Mediated Oxidative Cyclization. Li E, Hu Z, Song L, Yu W, Chang J. Chemistry 22 11022-11027 (2016)
  16. Ligand shape emerges in solvent dipole ordering region at ligand binding site of protein. Murata K, Nagata N, Nakanishi I, Kitaura K. J Comput Chem 31 791-796 (2010)


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