“…The QSAR model in eq 1 expressed that increased hydrophobicity and molecular bulkiness of amino acids in positions P3, P2, and P1′ give an increased degree of POP inhibition (lower IC 50 ). Earlier studies have indicated the importance of hydrophobicity of the side chain residues (21)(22)(23)(24).…”
Section: Resultsmentioning
confidence: 99%
“…The QSAR model in eq 1 expressed that increased hydrophobicity and molecular bulkiness of amino acids in positions P3, P2, and P1‘ give an increased degree of POP inhibition (lower IC 50 ). Earlier studies have indicated the importance of hydrophobicity of the side chain residues ( − ). 2 Predicted vs measured values for inhibition of POP by peptides derived from β-casein using the QSAR model (eq 1) indicating that hydrophobic and bulky amino acids adjacent to proline residues give inhibitory peptides ( R = 0.84, p < 0.001).…”
Quantitative structure-activity relationship (QSAR) modeling using simple amino acid descriptors was done on a set of prolyl oligopeptidase (POP) inhibitory peptides derived from beta-casein. Using partial least-squares regression, a QSAR model was obtained indicating that increased hydrophobicity and molecular bulkiness of amino acids in positions P3, P2, and P1' of inhibitory sites on peptides resulted in increased inhibition (lower IC50). Proline residues were always assumed to be in position P1. Hydrophobicity and molecular bulkiness have also in other studies been found as important factors for binding between substrates (or inhibitors) and the active site of POP. Prolyl oligopeptidase in blood serum is found to influence the level of hormone and neuropeptides and be related to cognitive and neurological deficiencies, e.g., Alzheimer's disease. Increased knowledge of the relationship between peptides derived from food proteins and their POP inhibition may be important in the development of functional foods as a supplement to pharmaceutical agents.
“…The QSAR model in eq 1 expressed that increased hydrophobicity and molecular bulkiness of amino acids in positions P3, P2, and P1′ give an increased degree of POP inhibition (lower IC 50 ). Earlier studies have indicated the importance of hydrophobicity of the side chain residues (21)(22)(23)(24).…”
Section: Resultsmentioning
confidence: 99%
“…The QSAR model in eq 1 expressed that increased hydrophobicity and molecular bulkiness of amino acids in positions P3, P2, and P1‘ give an increased degree of POP inhibition (lower IC 50 ). Earlier studies have indicated the importance of hydrophobicity of the side chain residues ( − ). 2 Predicted vs measured values for inhibition of POP by peptides derived from β-casein using the QSAR model (eq 1) indicating that hydrophobic and bulky amino acids adjacent to proline residues give inhibitory peptides ( R = 0.84, p < 0.001).…”
Quantitative structure-activity relationship (QSAR) modeling using simple amino acid descriptors was done on a set of prolyl oligopeptidase (POP) inhibitory peptides derived from beta-casein. Using partial least-squares regression, a QSAR model was obtained indicating that increased hydrophobicity and molecular bulkiness of amino acids in positions P3, P2, and P1' of inhibitory sites on peptides resulted in increased inhibition (lower IC50). Proline residues were always assumed to be in position P1. Hydrophobicity and molecular bulkiness have also in other studies been found as important factors for binding between substrates (or inhibitors) and the active site of POP. Prolyl oligopeptidase in blood serum is found to influence the level of hormone and neuropeptides and be related to cognitive and neurological deficiencies, e.g., Alzheimer's disease. Increased knowledge of the relationship between peptides derived from food proteins and their POP inhibition may be important in the development of functional foods as a supplement to pharmaceutical agents.
“…Introduction of carbonyl-containing Nheterocycles into the end of the alkyl chain of compounds 3 led to novel types of POP inhibitors 4 with nanomolar activities. 33,34 A comparative molecular field analysis study on 44 derivatives of 4 containing phthalimido (e.g., 5) or saccharino moieties as N-terminal group suggested some steric and electronic modifications on these N-heterocyclic end-groups 35 (Figure 2). However, as the interactions at subsite S3 of POP are nonspecific and difficult to predict, we decided to map these interactions in the structures of the complexes for derivatives 6, 8, and 11.…”
Section: Introductionmentioning
confidence: 99%
“…In our POP program, substitution of the 4-phenylbutanoyl of 2 with hexanoyl resulted in 3a with activity similar to that of 2 . − Substitution of the 4-CH 2 group of the proline moiety of 3a with a sulfur atom resulted in a derivative 3b that was 4 times more active. Introduction of carbonyl-containing N-heterocycles into the end of the alkyl chain of compounds 3 led to novel types of POP inhibitors 4 with nanomolar activities. , A comparative molecular field analysis study on 44 derivatives of 4 containing phthalimido (e.g., 5 ) or saccharino moieties as N-terminal group suggested some steric and electronic modifications on these N -heterocyclic end-groups (Figure ).…”
Three novel, N-acyl-pro-pyrrolidine-type, inhibitors of prolyl oligopeptidase (POP) with nanomolar activities were synthesized and their binding analyzed to the host enzyme in the light of X-ray diffraction and molecular modeling studies. We were interested in the alteration in the binding affinity at the S3 site as a function of the properties of the N-terminal group of the inhibitors. Our studies revealed that, for inhibitors with flat aromatic terminal groups, the optimal length of the linker chain is three C-C bonds, but this increases to four C-C bonds if there is a bulky group in the terminal position. Molecular dynamics calculations indicate that this is due to the better fit into the binding pocket. A 4-fold enhancement of the inhibitor activity upon replacement of the 4-CH2 group of the proline ring by CF2 is a consequence of a weak hydrogen bond formed between the fluorine atom and the hydroxy group of Tyr473 of the host enzyme. There is notably good agreement between the calculated and experimental free energies of binding; the average error in the IC50 values is around 1 order of magnitude.
“…Chemists play a significant role as medicinal chemists in the early stages, and as process chemists in the late stage of drug research. In 1999, at the First Italian-Hungarian-Polish Joint Meeting on Medicinal Chemistry at Giardini-Naxos, Sicily, we discussed the content and applications of the means of medicinal chemistry in the case of prolyl endopeptidase inhibitors [1,2].…”
A facile convergent total synthesis of the selective, potent, and orally active V 2 nonpeptide antagonist, SR-121463, was developed by modification of the discovery route. One of the late intermediates, the sulfonyl chloride 1, was synthesized from 3-hydroxybenzoic acid (19) by regioselective sulfonation, O-methylation and amidation in four steps. Another late intermediate, indolin-2-one 2, was prepared from p-phenetidine (8) through the indolin-2-one 16, where the cyclohexanone moiety of 27 was introduced into the active 3-methylene group of 16 by sequential transformation using methyl acrylate and KOtBu. After formation of the cyclic ketal moiety of 13, its ring-opening was achieved by using NaBH 4 in the presence of CCl 3 COOH. The morpholino group in 2 was introduced in accordance with the discovery approach, starting from the 2-hydroxyethoxy derivative 14 through the tosyloxy derivative 15 with morpholine in a one-pot reaction. In this way, the indolin-2-one 2 was synthesized from 8 in six steps. Finally, acylation of the indolin-2-one 2 was achieved with the sulfonyl chloride 1 in the presence of KOtBu in dimethyl sulfoxide (DMSO) at room temperature. This synthetic route proved to be applicable for the large-scale synthesis of SR-121463.
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