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Titolo:
Computer simulation of the interaction of non-steroidal anti-inflammatory drugs: Indoprofen and NS398 with cyclooxygenase
Autore:
Kothekar, V; Sahi, S; Srinivasan, M;
Indirizzi:
All India Inst Med Sci, Dept Biophys, New Delhi 110029, India All India Inst Med Sci New Delhi India 110029 s, New Delhi 110029, India
Titolo Testata:
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
fascicolo: 4, volume: 16, anno: 1999,
pagine: 901 -
SICI:
0739-1102(199902)16:4<901:CSOTIO>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROSTAGLANDIN H-2 SYNTHASE; ANTIINFLAMMATORY DRUGS; SELECTIVE-INHIBITION; CRYSTAL-STRUCTURE; NUCLEIC-ACIDS; ASPIRIN; DESIGN; SITE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
43
Recensione:
Indirizzi per estratti:
Indirizzo: Kothekar, V All India Inst Med Sci, Dept Biophys, Ansari Nagar, New Delhi 110029, India All India Inst Med Sci Ansari Nagar New Delhi India 110029 ia
Citazione:
V. Kothekar et al., "Computer simulation of the interaction of non-steroidal anti-inflammatory drugs: Indoprofen and NS398 with cyclooxygenase", J BIO STRUC, 16(4), 1999, pp. 901

Abstract

We have applied computer simulation technique to study interaction of two anti-inflammatory drugs (NSAIDs) indoprofen and NS398 with cyclooxygenase (COX-1 and COX-2) enzymes. We have also investigated conformational flexibility of the two drugs by systematic search and simulated annealing moleculardynamics (SAMD) methods. Both the drugs were docked in the cyclooxygenase channel using in house docking program IMF1. The complexes were energy minimised by molecular mechanics (MM) method. These were heated for 30 picoseconds (ps), equilibrated for 110 ps at 300K and subjected to 'production simulation' for 110 ps by molecular dynamics (MD) method using Sanderis module of AMBER 5.0 package and united atom force field mostly from PARM96.DAT. Integration was carried out with time step of 0.001 ps, distance dependent di-electric constant with scaling factor 2.0 for 1-4 interaction and cut-off distance for non-bonded pair-list equal to 8 Angstrom. The non-bonded pair-list was upgraded after every 20 cycles. The coordinate output from MD trajectories is analysed using analysis package of AMBER 5.0, MOLMOL, P-CURVES 3.0 and in house packages: ANALMD, ANALP1. We have observed perturbative changes in COX-1 and COX-2 structures due to indoprofen and NS398. In case ofindoprofen specific changes between COX-1 and COX-2 were noted in helix D,H6, S6 and helix H8 in the cyclooxygenase cavity. In case of NS398 these were in helix B in membrane binding domain, helix H6, S8 and S10 in cyclooxygenase cavity and helices H14-H16 in small lobe close to haem binding region. Implications of these results in enzyme selectivity by NSAIDs is discussed here.

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Documento generato il 21/09/20 alle ore 02:48:51