Comparative conformation-activity relationships for hormonally- and centrally-acting TRH analogues.
Empirical energy calculations have been applied to a series of thyrotrophin-releasing hormone (TRH) analogues in an attempt to incorporate the conformational parameter into traditional Quantitative Structure-Activity Relationships (QSAR). A search was made of the potential surface of each analogue using a SIMPLEX technique coupled with a model representing solvent effects as a dielectric continuum. Conformers of TRH can be described in terms of the distance between the pyroglutamyl, imidazole and prolyl rings, and presented as two-dimensional descriptor coordinates using multidimensional scaling. This process was repeated for stable and metastable conformers of all the TRH analogues investigated and correlated with experimental data on receptor affinity, relative stability and biological potency of the analogues. The results obtained suggest that modifications to the TRH structure can lead to greater potency in addition to improved stability, and that providing the appropriate theoretical approach is taken, it is possible to apply QSAR-based design procedures to conformationally-flexible drugs.
Ward
D J
DJ
Department of Biochemistry & Molecular Biology, School of Biological Sciences, University of Manchester, England.
Finn
P W
PW
Griffiths
E C
EC
Robson
B
B
D000818:Animals; D008958:Models, Molecular; D011487:Protein Conformation; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D018025:Receptors, Thyrotropin-Releasing Hormone; D012984:Software; D013329:Structure-Activity Relationship; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives*
D017981:Receptors, Neurotransmitter; D018025:Receptors, Thyrotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone