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Inhibition of trypsin and thrombin by amino(4-amidinophenyl)methanephosphonate diphenyl ester derivatives: X-ray structures and molecular models.

Bertrand JA, Oleksyszyn J, Kam CM, Boduszek B, Presnell S, Plaskon RR, Suddath FL, Powers JC, Williams LD
Biochemistry 35 3147-55 (1996)
Cited: 25 times
EuropePMC logo PMID: 8605148

Abstract

X-ray structures of trypsin from bovine pancreas inactivated by diphenyl [N-(benzyloxycarbonyl)amino](4-amidinophenyl)methanephosphonate [Z-(4-AmPhGly)P(OPh)2] were determined at 113 and 293 K to 1.8 angstrom resolution and refined to R factors of 0.211 (113 K) and 0. 178 (293 K). The structures reveal a tetrahedral phosphorus covalently bonded to the O gamma of the active site serine. Covalent bond formation is accompanied by the loss of both phenoxy groups. The D-stereoisomer of Z-(4-AmPhGly)P-(OPh)2 is not observed in the complex. The L-stereoisomer of the inhibitor forms contacts with several residues in the trypsin active site. One of the phosphonate oxygens is inserted into the oxyanion hole and forms hydrogen bonds to the amides of Gly193, Asp194, and Ser195. The second phosphonate oxygen forms hydrogen bonds to N epsilon 2 of His 57. The p-amidinophenylglycine moiety binds into the trypsin primary specificity pocket, interacting with Asp189. The amide forms a hydrogen bond to the carbonyl oxygen atom of Ser214. The inhibitor moiety, from the 113 K structure of trypsin inactivated by the reaction product of Z-(4-AmPhGly)P(OPh)2, was docked into human thrombin [Bode, W., Mayr, I., Baumann, U., Huber, R., Stone, S. R., & Hofsteenge, J. (1989) EMBO J. 8, 3467-3475] and energy minimized. The inhibitor fits well into the thrombin active site, forming favorable contacts similar to those in the trypsin complex with no bad contacts.

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  1. Recent Developments in Peptidyl Diaryl Phoshonates as Inhibitors and Activity-Based Probes for Serine Proteases. Maślanka M, Mucha A. Pharmaceuticals (Basel) 12 (2019)

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  1. The 1.8 A crystal structure of human cathepsin G in complex with Suc-Val-Pro-PheP-(OPh)2: a Janus-faced proteinase with two opposite specificities. Hof P, Mayr I, Huber R, Korzus E, Potempa J, Travis J, Powers JC, Bode W. EMBO J. 15 5481-5491 (1996)
  2. Remarkable potential of the α-aminophosphonate/phosphinate structural motif in medicinal chemistry. Mucha A, Kafarski P, Berlicki Ł. J. Med. Chem. 54 5955-5980 (2011)
  3. Structural and mechanistic insights into polyketide macrolactonization from polyketide-based affinity labels. Giraldes JW, Akey DL, Kittendorf JD, Sherman DH, Smith JL, Fecik RA. Nat. Chem. Biol. 2 531-536 (2006)
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  5. Inhibition of human alpha-thrombin by a phosphonate tripeptide proceeds via a metastable pentacoordinated phosphorus intermediate. Skordalakes E, Dodson GG, Green DS, Goodwin CA, Scully MF, Hudson HR, Kakkar VV, Deadman JJ. J. Mol. Biol. 311 549-555 (2001)
  6. New potent cathepsin G phosphonate inhibitors. Sieńczyk M, Lesner A, Wysocka M, Legowska A, Pietrusewicz E, Rolka K, Oleksyszyn J. Bioorg. Med. Chem. 16 8863-8867 (2008)
  7. Substrate modulation of enzyme activity in the herpesvirus protease family. Lazic A, Goetz DH, Nomura AM, Marnett AB, Craik CS. J. Mol. Biol. 373 913-923 (2007)
  8. The molecular basis of urokinase inhibition: from the nonempirical analysis of intermolecular interactions to the prediction of binding affinity. Grzywa R, Dyguda-Kazimierowicz E, Sieńczyk M, Feliks M, Sokalski WA, Oleksyszyn J. J Mol Model 13 677-683 (2007)
  9. A mechanism-based probe for gp120-Hydrolyzing antibodies. Taguchi H, Burr G, Karle S, Planque S, Zhou YX, Paul S, Nishiyama Y. Bioorg. Med. Chem. Lett. 12 3167-3170 (2002)
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  11. Isothermal titration calorimetry determination of individual rate constants of trypsin catalytic activity. Aguirre C, Condado-Morales I, Olguin LF, Costas M. Anal. Biochem. 479 18-27 (2015)
  12. A Fluorescent-Labeled Phosphono Bisbenzguanidine As an Activity-Based Probe for Matriptase. Häußler D, Schulz-Fincke AC, Beckmann AM, Keils A, Gilberg E, Mangold M, Bajorath J, Stirnberg M, Steinmetzer T, Gütschow M. Chemistry 23 5205-5209 (2017)
  13. Development and binding characteristics of phosphonate inhibitors of SplA protease from Staphylococcus aureus. Burchacka E, Zdzalik M, Niemczyk JS, Pustelny K, Popowicz G, Wladyka B, Dubin A, Potempa J, Sienczyk M, Dubin G, Oleksyszyn J. Protein Sci. 23 179-189 (2014)
  14. Is inhibition process better described with MD(QM/MM) simulations? The case of urokinase type plasminogen activator inhibitors. Barbault F, Maurel F. J Comput Chem 33 607-616 (2012)
  15. Phosphono Bisbenzguanidines as Irreversible Dipeptidomimetic Inhibitors and Activity-Based Probes of Matriptase-2. Häußler D, Mangold M, Furtmann N, Braune A, Blaut M, Bajorath J, Stirnberg M, Gütschow M. Chemistry 22 8525-8535 (2016)
  16. Phosphoramidates as novel activity-based probes for serine proteases. Haedke UR, Frommel SC, Hansen F, Hahne H, Kuster B, Bogyo M, Verhelst SH. Chembiochem 15 1106-1110 (2014)
  17. Synthesis and kinetic studies of an amidine-containing phosphonofluoridate: a novel potent inhibitor of trypsin-like enzymes. Ni LM, Powers JC. Bioorg. Med. Chem. 6 1767-1773 (1998)
  18. Covalent inactivation of factor VIII antibodies from hemophilia A patients by an electrophilic FVIII Analog. Planque S, Escobar MA, Smith KC, Taguchi H, Nishiyama Y, Donnachie E, Pratt KP, Paul S. J. Biol. Chem. 283 11876-11886 (2008)
  19. Modulation of human alpha-thrombin activity with phosphonate ester inhibitors. Enyedy EJ, Kovach IM. Bioorg. Med. Chem. 5 1531-1541 (1997)
  20. Activity-based protein profiling reveals active serine proteases that drive malignancy of human ovarian clear cell carcinoma. Mehner C, Hockla A, Coban M, Madden B, Estrada R, Radisky DC, Radisky ES. J Biol Chem 298 102146 (2022)
  21. Site-Selective Incorporation of a Functional Group into Lys175 in the Vicinity of the Active Site of Chymotrypsin by Using Peptidyl α-Aminoalkylphosphonate Diphenyl Ester-Derivatives. Ono S, Koga M, Arimura Y, Hatakeyama T, Kobayashi M, Sagara JI, Nakai T, Horino Y, Kuroda H, Oyama H, Arima K. Molecules 28 3150 (2023)


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