In the work the conformational-electronic aspects important for the functional activity of deltorphin I and deltorphin II are investigated by the methods of molecular mechanics, molecular dynamics and quantum chemistry using modern computer programs. It was established that the stability of the spatial structure of deltorphins is determined by the mutual arrangement of the pharmacophore elements: α-amino group, phenolic ring of Tyr1 residue, aromatic ring of Phe3 residue, negatively charged Asp/Glu residue groups and characterized by a specific distribution of electron density, which plays an important role in the interaction with receptor. Based on the obtained results and data of structure-function relationships, the biologically active conformations of deltorphins were assessed and a pharmacophore model was constructed for their binding to δ- receptors. It is shown that the biologically active conformations of these molecules are characterized by a semi-folded form of the main chain: in them the C-terminal fragment Val-Val-Gly-NH2, which has an elongated conformation, due to reverse turn on the Val5 residue in space is close to the N-terminal helical fragment Tyr-D -Ala-Phe-Asp/Glu, that makes these molecules compact. It can be assumed that for the analgesic action of deltorphins the sterically probable spatial structures of their N-terminal physiologically active tetrapeptide fragment which are stabilized by salt bridges between the protonated nitrogen atom and the oxygen atoms of the side chains of negatively charged Asp/Glu residues are responsible, while binding to the receptors is formed by the formation of hydrogen bonds with involving ionizable functional groups.
deltorphins, biologically active conformation, pharmacophore model, computer modelling methods
1. Erspamer V., Melchiorri P., Falconieri-Erspamer G. et al. Deltorphins: A family of naturally occurring peptides with high affinity and selectivity for delta opioid binding sites. Proc. Natl. Acad. Sci. USA, 1989, vol. 86, iss. 13, pp. 5188-5192.
2. Heyl D., Schullery S., Renganathan K. et al. pKa and Volume of residue one influence opioid binding: QSAR analysis of tyrosine replacement in a nonselective deltorphin analogue. Bioorganic & Medicinal Chemistry, 2003, vol. 11, pp. 3761-3768.
3. Schullery S., Mohammdshah T., Makhlouf H. et al. Binding to δ and opioid receptors by deltorphin I/II analogues modified at the Phe3 and Asp4/Glu4 side chains: a report of 32 new analogues and a QSAR study. J. Biomol. Struct. Dyn., 1999, vol. 17, iss. 3, pp. 445-460.
4. Schullery S., Rodgers D., Tripathy S. et al. The role of backbone conformation in deltorphin II binding: A QSAR study of new analogues modified in the 5-, 6-positions of the address domain. Bioorganic & Medicinal Chemistry, 2001, vol. 9, iss. 10, pp. 2633-2642.
5. Thomas S., Abbruscato T., Hau V. et al. Structure-activity relationships of a series of [D-Ala2]deltorphin I and II analogues; in vitro blood-brain barrier permeability and stability. J. Pharmacol. Exp. Ther., 1997, vol. 281, pp. 817-825.
6. Ohno Y., Segawa M., Ohishi et al. Conformation of of deltorphin-II in membrane environment studied by two-dimensional NMR spectroscopy and molecular dynamics calculations. European Journal of Biochemistry, 1993, vol. 212, iss. 1, pp. 185-191.
7. Riand J., Baron D., Nicolas P. et al. The δ-selective opioid peptide dermenkephalin delta-selective opioid peptide dermenkephalin and the μ-selective hybrid peptide dermenkephalin-[1-4]-dermophin-[5-7] display strikingly different conformations despite identical tetrapeptide N-termini. A quantitative 2-D NMR and molecular modeling analysis. Journal of Biomolecular Structure & Dynamics, 2000, vol. 17, iss. 3, pp. 445-460.
8. Segawa M., Ohno Y., Doi M. et al. Comparative conformational analyses of mu-selective dermorphin and delta-selective deltorphin-II in aqueous solution by 1H-NMR spectroscopy. Biomol. Struct. Dyn., 2003, vol. 17, iss. 3, pp.445-460.
9. Fadhil I., Schmidt R., Walpole C. et al. Exploring Deltorphin II Binding to the Third Extracellular Loop of the-Opioid Receptor. J. Biol. Chem., 2004, vol. 279, iss. 20, pp. 21069-21077.
10. Akverdieva G.A. Insights into spatial structure of deltorphins. Journal of Qafqaz University, 2016, vol. 4, no. 1, pp. 13-20.
11. Godzhaev N.M., Maksumov I.C., Ismailova L.I. Programma poluempiricheskogo rascheta konformaciy molekulyarnyh kompleksov. Zhurnal strukturnoy himii, 1983, t. 24, № 4, s. 147-148 [Godjayev N.M., Maksumov I.S., Ismailova L.I., Programm of semiempirical calculations of conformations of molecular complexes. J. Struct. Chem., vol. 4, 1983, pp. 147-148. (In Russ.)]
12. Shaitan K.V., Saraykin S.S. Molecular dynamics method, 1999. URL: http://www.moldyn.ru (In Russ.)
13. Allinger N.L., Yuh Y., QCPE 395, Quantum chemistry program exchange. Indiana Univ., Indiana, 1982.
14. Lodyga-Chruscinsca E., Oldziej S., Micera G. et al. Effects of tetra zole moiety on coordinating efficiency of deltorphin. Acta Biochimica Polonica, 2004, vol. 51, no. 1, pp. 93-106.
15. Schullery S., Rodgers D., Tripathy S. et al. The role of backbone conformation in deltorphin II binding: A QSAR study of new analogues modified in the 5-, 6-positions of the address. Bioorganic & Medicinal Chemistry, 2001, vol. 9, iss. 10, pp. 2633-2642.
