1o2k › Citations

Elaborate manifold of short hydrogen bond arrays mediating binding of active site-directed serine protease inhibitors.

Katz BA, Elrod K, Verner E, Mackman RL, Luong C, Shrader WD, Sendzik M, Spencer JR, Sprengeler PA, Kolesnikov A, Tai VW, Hui HC, Breitenbucher JG, Allen D, Janc JW
J Mol Biol 329 93-120 (2003)

Cited: 22 times
EuropePMC logo PMID: 12742021

Abstract

An extensive structural manifold of short hydrogen bond-mediated, active site-directed, serine protease inhibition motifs is revealed in a set of over 300 crystal structures involving a large suite of small molecule inhibitors (2-(2-phenol)-indoles and 2-(2-phenol)-benzimidazoles) determined over a wide range of pH (3.5-11.4). The active site hydrogen-bonding mode was found to vary markedly with pH, with the steric and electronic properties of the inhibitor, and with the type of protease (trypsin, thrombin or urokinase type plasminogen activator (uPA)). The pH dependence of the active site hydrogen-bonding motif is often intricate, constituting a distinct fingerprint of each complex. Isosteric replacements or minor substitutions within the inhibitor that modulate the pK(a) of the phenol hydroxyl involved in short hydrogen bonding, or that affect steric interactions distal to the active site, can significantly shift the pH-dependent structural profile characteristic of the parent scaffold, or produce active site-binding motifs unique to the bound analog. Ionization equilibria at the active site associated with inhibitor binding are probed in a series of the protease-inhibitor complexes through analysis of the pH dependence of the structure and environment of the active site-binding groups involved in short hydrogen bond arrays. Structures determined at high pH (>11), suggest that the pK(a) of His57 is dramatically elevated, to a value as high as approximately 11 in certain complexes. K(i) values involving uPA and trypsin determined as a function of pH for a set of inhibitors show pronounced parabolic pH dependence, the pH for optimal inhibition governed by the pK(a) of the inhibitor phenol involved in short hydrogen bonds. Comparison of structures of trypsin, thrombin and uPA, each bound by the same inhibitor, highlights important structural variations in the S1 and active sites accessible for engineering notable selectivity into remarkably small molecules with low nanomolar K(i) values.

Articles - 1o2k mentioned but not cited (3)

  1. A knowledge-guided strategy for improving the accuracy of scoring functions in binding affinity prediction. Cheng T, Liu Z, Wang R. BMC Bioinformatics 11 193 (2010)
  2. Synthesis and structure-activity relationship studies of novel dihydropyridones as androgen receptor modulators. Pepe A, Pamment M, Kim YS, Lee S, Lee MJ, Beebe K, Filikov A, Neckers L, Trepel JB, Malhotra SV. J Med Chem 56 8280-8297 (2013)
  3. Path-integral method for predicting relative binding affinities of protein-ligand complexes. Mulakala C, Kaznessis YN. J Am Chem Soc 131 4521-4528 (2009)


Articles citing this publication (19)

  1. Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS-STING signalling. Eaglesham JB, Pan Y, Kupper TS, Kranzusch PJ. Nature 566 259-263 (2019)
  2. Expression, crystallization, and three-dimensional structure of the catalytic domain of human plasma kallikrein. Tang J, Yu CL, Williams SR, Springman E, Jeffery D, Sprengeler PA, Estevez A, Sampang J, Shrader W, Spencer J, Young W, McGrath M, Katz BA. J Biol Chem 280 41077-41089 (2005)
  3. Selectivity of neutral/weakly basic P1 group inhibitors of thrombin and trypsin by a molecular dynamics study. Wu EL, Han K, Zhang JZ. Chemistry 14 8704-8714 (2008)
  4. Could MM-GBSA be accurate enough for calculation of absolute protein/ligand binding free energies? Mulakala C, Viswanadhan VN. J Mol Graph Model 46 41-51 (2013)
  5. Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA). Katz BA, Luong C, Ho JD, Somoza JR, Gjerstad E, Tang J, Williams SR, Verner E, Mackman RL, Young WB, Sprengeler PA, Chan H, Mortara K, Janc JW, McGrath ME. J Mol Biol 344 527-547 (2004)
  6. Factor VIIa inhibitors: a prodrug strategy to improve oral bioavailability. Riggs JR, Kolesnikov A, Hendrix J, Young WB, Shrader WD, Vijaykumar D, Stephens R, Liu L, Pan L, Mordenti J, Green MJ, Sukbuntherng J. Bioorg Med Chem Lett 16 2224-2228 (2006)
  7. Application of a polarizable force field to calculations of relative protein-ligand binding affinities. Khoruzhii O, Donchev AG, Galkin N, Illarionov A, Olevanov M, Ozrin V, Queen C, Tarasov V. Proc Natl Acad Sci U S A 105 10378-10383 (2008)
  8. Scoring ligand similarity in structure-based virtual screening. Zavodszky MI, Rohatgi A, Van Voorst JR, Yan H, Kuhn LA. J Mol Recognit 22 280-292 (2009)
  9. Exploring conformational search protocols for ligand-based virtual screening and 3-D QSAR modeling. Cappel D, Dixon SL, Sherman W, Duan J. J Comput Aided Mol Des 29 165-182 (2015)
  10. Comparative binding energy analysis for binding affinity and target selectivity prediction. Henrich S, Feierberg I, Wang T, Blomberg N, Wade RC. Proteins 78 135-153 (2010)
  11. Evaluation of docking performance in a blinded virtual screening of fragment-like trypsin inhibitors. Surpateanu G, Iorga BI. J Comput Aided Mol Des 26 595-601 (2012)
  12. Factor VIIa inhibitors: gaining selectivity within the trypsin family. Shrader WD, Kolesnikov A, Burgess-Henry J, Rai R, Hendrix J, Hu H, Torkelson S, Ton T, Young WB, Katz BA, Yu C, Tang J, Cabuslay R, Sanford E, Janc JW, Sprengeler PA. Bioorg Med Chem Lett 16 1596-1600 (2006)
  13. Prediction of trypsin/molecular fragment binding affinities by free energy decomposition and empirical scores. Benson ML, Faver JC, Ucisik MN, Dashti DS, Zheng Z, Merz KM. J Comput Aided Mol Des 26 647-659 (2012)
  14. Estimating the Roles of Protonation and Electronic Polarization in Absolute Binding Affinity Simulations. King E, Qi R, Li H, Luo R, Aitchison E. J Chem Theory Comput 17 2541-2555 (2021)
  15. Exploration of conformational transition in the aryl-binding site of human FXa using molecular dynamics simulations. Wang JF, Hao P, Li YX, Dai JL, Li X. J Mol Model 18 2717-2725 (2012)
  16. Quantitative expression of protein heterogeneity: Response of amino acid side chains to their local environment. Bandyopadhyay D, Mehler EL. Proteins 72 646-659 (2008)
  17. SHOP: a method for structure-based fragment and scaffold hopping. Fontaine F, Cross S, Plasencia G, Pastor M, Zamora I. ChemMedChem 4 427-439 (2009)
  18. Small molecule inhibitors of plasma kallikrein. Young WB, Rai R, Shrader WD, Burgess-Henry J, Hu H, Elrod KC, Sprengeler PA, Katz BA, Sukbuntherng J, Mordenti J. Bioorg Med Chem Lett 16 2034-2036 (2006)
  19. Discovery of novel hydroxy pyrazole based factor IXa inhibitor. Vijaykumar D, Sprengeler PA, Shaghafi M, Spencer JR, Katz BA, Yu C, Rai R, Young WB, Schultz B, Janc J. Bioorg Med Chem Lett 16 2796-2799 (2006)


Quick links