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Titolo:
The structural and electronical factors that contribute affinity for the time-dependent inhibition of PGHS-1 by indomethacin, diclofenac and fenamates
Autore:
Pouplana, R; Perez, C; Sanchez, J; Lozano, JJ; Puig-Parellada, P;
Indirizzi:
Univna,rcelona, Fac Farm, Unitat Fisicoquim, Dept Farmacia, E-08028 Barcelo Univ Barcelona Barcelona Spain E-08028 m, Dept Farmacia, E-08028 Barcelo UAB, Fac Med, IMIM, Dept Med Informat, E-08003 Barcelona, Spain UAB Barcelona Spain E-08003 Dept Med Informat, E-08003 Barcelona, Spain
Titolo Testata:
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
fascicolo: 3, volume: 13, anno: 1999,
pagine: 297 - 313
SICI:
0920-654X(199905)13:3<297:TSAEFT>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROSTAGLANDIN-G/H SYNTHASE-1; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CYCLOOXYGENASE ACTIVE-SITE; H SYNTHASE-1; CONFORMATIONAL-ANALYSIS; ENDOPEROXIDE SYNTHASE; SELECTIVE-INHIBITION; CRYSTAL-STRUCTURE; H-2 SYNTHASE; BINDING;
Keywords:
anti-inflammatory agents; cyclooxygenase inhibitors; fenamates; PGHS-1; QSAR modeling;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Pouplana, R Univ-N,rcelona, Fac Farm, Unitat Fisicoquim, Dept Farmacia, AvJoan XXIII,S Univ Barcelona Av Joan XXIII,S-N Barcelona Spain E-08028 II,S
Citazione:
R. Pouplana et al., "The structural and electronical factors that contribute affinity for the time-dependent inhibition of PGHS-1 by indomethacin, diclofenac and fenamates", J COMPUT A, 13(3), 1999, pp. 297-313

Abstract

PGHS-1 and PGHS-2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs). It appears that the high degree of selectivity for inhibition of PGHS-2 shown by certain compounds is the result of two mechanisms (time-dependent and time-independent inhibition), by which they interact with each isoform. The fenamic acids can be divided into competitive inhibitors of substrate binding and competitive inhibitors that cause time-dependent losses of cyclooxygenase activity. The cyclooxygenase activity was measured by oxygen consumption following preincubation of the enzyme and the inhibitor forincreasing periods of time. The rate constants associated with binding inhibition kinetics and structure-activity relationships were calculated for alarge number of fenamates, diclofenac and indomethacin. The K-I* values are similar but the individual rate constants are markedly different: k(1) istwo-fold lower, and k(2) is six-fold slower for diclofenac than for indomethacin. All the active time-dependent compounds show MEPs with a negative conical surface, with their vertex on the minimum of the carboxyl group, which extends around the first aromatic ring to the central region. The conical surface keeps an open angle of 61 degrees or larger, and a close contact surface with the residues Ala(527), Ileu(523), Val(349), and Ser(530), in the zones surrounding the bridging amino group and the chlorine atoms for meclofenamate and diclofenac, or in the region around the carbonyl group for indomethacin. The K-I* and IC50 values indicate that the interactions that promote the slow binding kinetics must be examined in relation to the reaction energies of formation (Delta H-r) of an ionic bond between the deprotonated carboxylic acid group of acid NSAIDs with the monocationic guanidinum group of Arg(120), the free energies of solvation in aqueous solution, and the molecular volumes measured. Presumably indomethacin, diclofenac and meclofenamate cause the enzyme to undergo a subtle conformational change to a form that binds compounds even more tightly, with some slight structural changes confined to reorientations of the Arg(277) and Gln(358) side chains. These results show that the model has reliably chosen regions of biologicalsignificance consistent with both the X-ray crystallographic and kinetic results.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 15/07/20 alle ore 13:39:17