Nonpeptidic Inhibitors of Human Leukocyte Elastase. 6. Design of a Potent, Intratracheally Active, Pyridone-Based Trifluoromethyl Ketone

Bernstein, Peter R; Gomes, Bruce; Kosmider, Benedict J.; Vacek, Edward P.; Williams, Joseph C.

doi:10.1021/jm00001a028

Cited by 44 publications

(26 citation statements)

References 2 publications

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“…To enable the goals of this work, we propose a small number of protein–ligand complexes that can be used to explore the potential polarizability of protein binding sites. Nine protein classes of pharmaceutical interest corresponding to 54 proteins6–56 were selected, and the data set is summarized in Table I. They comprise a wide range of functional activity: hydrolases (proteases), transferases (kinase and phosphatase), oxidoreductases (reductases), and receptors (NHR, rhodopsin).…”

Section: Methodsmentioning

confidence: 99%

An assessment of protein–ligand binding site polarizability

Nayeem¹,

Krystek²,

Stouch³

2003

Biopolymers

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Electronic polarizability, an important physical property of biomolecules, is currently ignored in most biomolecular calculations. Yet, it is widely believed that polarization could account for a substantial fraction of the total nonbonded energy of a system. This belief is supported by studies of small complexes in vacuum. This perception is driving the development of a new class of polarizable force fields for biomolecular calculations. However, the quantification of this term for protein-ligand complexes has never been attempted. Here we explore the polarizable nature of protein-ligand complexes in order to evaluate the importance of this effect. We introduce two indexes describing the polarizability of protein binding sites. These we apply to a large range of pharmaceutically relevant complexes. We offer a recommendation of particular complexes as test systems with which to determine the effects of polarizability and as test cases with which to test the new generation of force fields. Additionally, we provide a tabulation of the amino acid composition of these binding sites and show that composition can be specific for certain classes of proteins. We also show that the relative abundance of some amino acids is different in binding sites than elsewhere in a protein's structure.

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Section: Methodsmentioning

confidence: 99%

An assessment of protein–ligand binding site polarizability

Nayeem¹,

Krystek²,

Stouch³

2003

Biopolymers

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“…This conformation would be expected, of course, on steric and electrostatic grounds and has been observed in serine protease/trifluoroketone complexes (for example, in reference 55). One fluorine atom is directed out of the active site into solvent where it might well interact with water molecules in the manner observed in a variety of crystal structures (55)(56)(57)(58). Such interactions are probably more dipolar in nature than involving classical hydrogen bonding and are probably of ca 1 kcal/mol strength (59,60).…”

Section: Crystal Structure Of the Complex Of The R39 Dd-peptidase Witmentioning

confidence: 99%

Inhibition of dd-Peptidases by a Specific Trifluoroketone: Crystal Structure of a Complex with the Actinomadura R39 dd-Peptidase

et al. 2013

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Inhibitors of bacterial DD-peptidases represent potential antibiotics. In the search for alternatives to β-lactams, we have investigated a series of compounds designed to generate transition state analogue structures on reaction with DD-peptidases. The compounds contain a combination of a peptidoglycan-mimetic specificity handle and a warhead capable of delivering a tetrahedral anion to the enzyme active site. The latter include a boronic acid, two alcohols, an aldehyde and a trifluoroketone. The compounds were tested against two low molecular mass class C DD-peptidases. As expected from previous observations, the boronic acid was a potent inhibitor, but, rather unexpectedly from precedent, the trifluoroketone [D-α-aminopimelyl-(1,1,1-trifluoro-3-amino)butan-2-one] was also very effective. Taking into account competing hydration, the trifluoroketone was the strongest inhibitor of the Actinomadura R39 DD-peptidase, with a subnanomolar (free ketone) inhibition constant. A crystal structure of the complex between the trifluoroketone and the R39 enzyme showed that a tetrahedral adduct had indeed formed with the active site serine nucleophile. The trifluoroketone moiety, therefore, should be considered along with boronic acids and phosphonates, as a warhead that can be incorporated into new and effective DD-peptidase inhibitors and therefore, perhaps, antibiotics.

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“…The pyridone ring is an example of such a scaffold and acts as a P3 to P2 conformational restraint. 317,318 Subsequent crystallography studies of 126 bound to PPE 316 (PDB entry: 1eas) demonstrated the successful retention of this hydrogen-bonding pattern, 319 via -sheet hydrogen bonds between the pyridone carbonyl oxygen and the pyridone 3-amino nitrogen with PPE. 317,318 Subsequent crystallography studies of 126 bound to PPE 316 (PDB entry: 1eas) demonstrated the successful retention of this hydrogen-bonding pattern, 319 via -sheet hydrogen bonds between the pyridone carbonyl oxygen and the pyridone 3-amino nitrogen with PPE.…”

Section: Ligands Containing One Ring With One Heteroatom (N)mentioning

confidence: 99%