Irreversible Enzyme Inhibitors. CVI.<sup>1</sup> Proteolytic Enzymes. I. Bulk Tolerances in Trypsin-Inhibitor Complexes<sup>2</sup>

Baker, B. R.; Erickson, Edward H.

doi:10.1021/jm00318a030

Cited by 18 publications

(8 citation statements)

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“…The ability of benzamidine to inhibit serine proteases of the trypsin family is well documented (35)(36)(37). This moiety, an isostere for the guanidine side chain of arginine, binds readily to the P 1 pocket via an amidine͞carboxylate salt bridge with the aspartic acid at the base of this pocket.…”

Section: Resultsmentioning

confidence: 99%

Potent selective nonpeptidic inhibitors of human lung tryptase

Burgess

Newhouse

Rizzi

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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Human lung tryptase, a homotetrameric serine protease unique to mast cell secretory granules, has been implicated in the pathogenesis of asthma. A hypothesis that tethered symmetrical inhibitors might bridge two adjacent active sites was explored via a rationally designed series of bisbenzamidines. These compounds demonstrated a remarkable distanced-defined structure-activity relationship against human tryptase with one series possessing subnanomolar potencies. Additional evidence supporting the concept of active-site bridging is also presented.

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Section: Resultsmentioning

confidence: 99%

Potent selective nonpeptidic inhibitors of human lung tryptase

Burgess

Newhouse

Rizzi

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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“…For a number of cases contained in the present dataset, several measurements of binding constants were published that show a spread of the experimental values of up to a factor of five [25,27,69]. This uncertainty of the experimental binding data poses a limit for the accuracy of any theoretical description of the binding data.…”

Section: Discussionmentioning

confidence: 99%

The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure

Böhm¹

1994

J Computer-Aided Mol Des

977

525

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A new simple empirical function has been developed that estimates the free energy of binding for a given protein-ligand complex of known 3D structure. The function takes into account hydrogen bonds, ionic interactions, the lipophilic protein-ligand contact surface and the number of rotatable bonds in the ligand. The dataset for the calibration of the function consists of 45 protein-ligand complexes. The new energy function reproduces the binding constants (ranging from 2.5.10(-2) to 4.10(-14) M, corresponding to binding energies between -9 and -76 kJ/mol) of the dataset with a standard deviation of 7.9 kJ/mol, corresponding to 1.4 orders of magnitude in binding affinity. The individual contributions to protein-ligand binding obtained from the scoring function are: ideal neutral hydrogen bond: -4.7 kJ/mol; ideal ionic interaction: -8.3 kJ/mol; lipophilic contact: -0.17 kJ/mol A2; one rotatable bond in the ligand: +1.4 kJ/mol. The function also contains a constant contribution (+5.4 kJ/mol) which may be rationalized as loss of translational and rotational entropy. The function can be evaluated very fast and is therefore also suitable for application in a 3D database search or de novo ligand design program such as LUDI.

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“…All 4 molecules form at least 2 hydrogen bonds with trypsin. It is interesting to note, that all these structures are known to bind into the specificity pockets of trypsin-like serine proteases [33,34].…”

Section: Trypsin Benzamidine Complexmentioning

confidence: 99%

The computer program LUDI: A new method for the de novo design of enzyme inhibitors

Böhm¹

1992

J Computer-Aided Mol Des

791

288

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A new computer program is described, which positions small molecules into clefts of protein structures (e.g. an active site of an enzyme) in such a way that hydrogen bonds can be formed with the enzyme and hydrophobic pockets are filled with hydrophobic groups. The program works in three steps. First it calculates interaction sites, which are discrete positions in space suitable to form hydrogen bonds or to fill a hydrophobic pocket. The interaction sites are derived from distributions of nonbonded contacts generated by a search through the Cambridge Structural Database. An alternative route to generate the interaction sites is the use of rules. The second step is the fit of molecular fragments onto the interaction sites. Currently we use a library of 600 fragments for the fitting. The final step in the present program is the connection of some or all of the fitted fragments to a single molecule. This is done by bridge fragments. Applications are presented for the crystal packing of benzoic acid and the enzymes dihydrofolate reductase and trypsin.

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Irreversible Enzyme Inhibitors. CVI.¹ Proteolytic Enzymes. I. Bulk Tolerances in Trypsin-Inhibitor Complexes²

Cited by 18 publications

References 0 publications

Potent selective nonpeptidic inhibitors of human lung tryptase

Potent selective nonpeptidic inhibitors of human lung tryptase

The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure

The computer program LUDI: A new method for the de novo design of enzyme inhibitors

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Irreversible Enzyme Inhibitors. CVI.1 Proteolytic Enzymes. I. Bulk Tolerances in Trypsin-Inhibitor Complexes2

Cited by 18 publications

References 0 publications

Potent selective nonpeptidic inhibitors of human lung tryptase

Potent selective nonpeptidic inhibitors of human lung tryptase

The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure

The computer program LUDI: A new method for the de novo design of enzyme inhibitors

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Product

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Irreversible Enzyme Inhibitors. CVI.¹ Proteolytic Enzymes. I. Bulk Tolerances in Trypsin-Inhibitor Complexes²