Three-dimensional quantitative structure-activity relationships of somatostatin analogues. 1. Comparative molecular field analysis of growth hormone release-inhibiting potencies.
Somatostatin is a hypothalamic hormone that inhibits the release of growth hormone (GH). It has also been shown to inhibit the release of a broad range of hormones including insulin, glucagon, and gastrin. Presently, five different receptor subtypes of somatostatin have been characterized and cloned. Our previous work on the structure-activity relationship of somatostatin and that of many others has generated a large database of analogues with different biological activities and receptor affinities. This present work is an investigation of the growth hormone release-inhibiting potencies of somatostatin analogues by the three-dimensional quantitative structure-activity paradigm, comparative molecular field analysis (CoMFA). A total of 64 analogues were modeled in SYBYL using structural information from two NMR studies. The molecules were aligned by a root-mean-square fit of atoms and field-fit of the steric and electrostatic molecular fields and the resulting databases analyzed by partial least squares analysis with cross-validation to extract the optimum number of components. The analysis was then repeated without cross-validation to give the final QSAR models. Preliminary investigations with the CoMFA models led to the synthesis of a new somatostatin analogue. This compound together with five other newly synthesized compounds not included in the original training sets were used to test the predictive ability of the CoMFA models. Two models with good predictive powers are presented.
Hocart
S J
SJ
Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Reddy
V
V
Murphy
W A
WA
Coy
D H
DH
D000595:Amino Acid Sequence; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D013006:Growth Hormone / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D012996:Solutions; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D009842:Oligopeptides; D012996:Solutions; D013004:Somatostatin; D013006:Growth Hormone