Modelling drug-receptor interactions in an average binding site for NK2

• Autorzy: Alagona G. , Ghio C. , Monti S.
• Języki publikacji: EN

Abstrakty

EN

A tentative procedure applied to the search for a new antagonist of neurokinin A (NKA) is presented. In parallel a tentative 3-D model of the NK2 receptor was created, using bacteriorhodopsin (BRD) as a template. The residue substitutions were performed in BRD to obtain the sequence for NK2R_H and the seven a-helical segments were optimized forcing the a-helical backbone to match the corresponding aligned parts of BRD, while the arrangements of the side chains were model built based on available site-directed mutagenesis studies. Constrained MM and molecular dynamics simulations were carried out H-bonding a low energy conformer of the known drugs to residues in the receptor site, allowing both the receptor site and drugs to relax. The Connolly surface for each ligand allowed to determine an "average" binding site in which all the low energy conformers of known and prospective drugs were docked and classified according to a statistical index. The whole procedure was repeated exploiting the lately published structure of an actual G protein coupled receptor as a better template, thus producing a cavity in the binding site to directly dock the drugs. Corollary validations of the force fields used are also mentioned. In addition intra- and intermolecular interactions suitable to produce more active drugs were evaluated.

Słowa kluczowe

EN

receptor modelling; docking; non covalent interactions; molecular mechanics; molecular dynamics; substituent effects

• Wydawca: Politechnika Gdańska
• Czasopismo: TASK Quarterly : scientific bulletin of Academic Computer Centre in Gdansk
• Rocznik: 1998
• Tom: Vol. 2, No 4
• Strony: 563--581
• Opis fizyczny: Bibliogr. 54 poz., rys., tab.

Twórcy

autor

Alagona G.

• CNR - ICQEM, Institute of Quantum Chemistry and Molecular Energetics, Via Risorgimento 35, I-56126 Pisa, Italy

autor

Ghio C.

• CNR - ICQEM, Institute of Quantum Chemistry and Molecular Energetics, Via Risorgimento 35, I-56126 Pisa, Italy

autor

Monti S.

• Menarini Ricerche SpA, Via Sette Santi 3, 1-50131 Florence, Italy

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