Keywords: Complexation, Hydrolysis, Molecular Structure, Proteins, Synthesis (chemical), Inhibition Constants, Biochemistry, Acid Halide, Aminoguanidine, Carbamoyl Chloride Derivative, Hirugen, N Diphenylcarbamoylguanidine, Phenyl Group, Proteinase, Serine, Serine Proteinase Inhibitor, Thrombin, Thrombin Inhibitor, Trypsin, Unclassified Drug, Article, Binding Affinity, Catalysis, Chemical Reaction, Covalent Bond, Crystal Structure, Measurement, Priority Journal, Protein Binding, Protein Function, Protein Interaction, Protein Structure, Structure Analysis, X Ray Crystallography, Anticoagulants, Competitive, X-Ray, Humans, Hydrogen-Ion Concentration, Kinetics, Models, Tertiary,
Affiliations: *** IBB - CNR ***
Ist. di Biostrutture/Bioimmagini-CNR, Via Mezzocannone 6, 80134 Napoli, Italy
Lab. di Chim. Inorg. e Bioinorganica, Università degli Studi, Via della Lastruccia 3, 50019 Sesto Fiorentino (Firenze), Italy
References: Not available.
Design of weakly basic thrombin inhibitors incorporating novel P1 binding functions: Molecular and X-ray crystallographic studies
To prepare weakly basic thrombin inhibitors with modified SI anchoring groups, two series of compounds were synthesized by reaction of guanidine or aminoguanidine with acyl halides and N,N-disubstituted carbamoyl chlorides. pK(a) measurements of these acylated guanidines/aminoguanidines showed a reduced basicity, with pKa values in the range of 8.4-8.7. These molecules typically showed inhibition constants in the range of 150-425 nM against thrombin and 360-965 nM against trypsin, even though some bulky derivatives, such as N,N-diphenylcarbamoylguanidine/aminoguanidine and their congeners, showed much stronger thrombin inhibitory activity, with inhibition constants in the range of 24-42 nM. Unexpectedly, very long incubation times with both proteases revealed that aminoguanidine derivatives behaved as irreversible inhibitors. To assess the molecular basis responsible for the high affinity observed for these molecules toward thrombin, the crystal structure of the thrombin - hirugen-N,N-diphenylcarbarnoylaminoguanidine complex has been solved at 1.90 Angstrom resolution. The structural analysis of the complex revealed an unexpected interaction mode with the protease, resulting in an N,N-diphenylcarbamoyl intermediate covalently bound to the catalytic serine as a consequence of its hydrolysis together with the release of the aminoguanidine moiety. Surprisingly, in this covalent adduct a phenyl group was found in the S1 specificity pocket, which usually recognizes positively charged residues. These findings provide new insights in the design of low basicity serine protease inhibitors.
Design of weakly basic thrombin inhibitors incorporating novel P1 binding functions: Molecular and X-ray crystallographic studies
No results.
Design of weakly basic thrombin inhibitors incorporating novel P1 binding functions: Molecular and X-ray crystallographic studies
Kállay C, Dávid A, Timári S, Nagy EM, Sanna D, Garribba E, Micera G, De Bona P, Pappalardo G, Rizzarelli E, Sóvágó I * Copper(II) complexes of rat amylin fragments(572 views) Dalton T (ISSN: 1477-9234, 1477-9226, 1477-9234electronic), 2011 Oct 14; 40(38): 9711-9721. Impact Factor:3.838 ViewExport to BibTeXExport to EndNote