in only 51 protein structures. Thus, the statistical analysis of of the remaining compounds decrease to the same degree protein structures supports the hypothesis that proteins fold that their geometries and MEP are different from those of in consistency with biosynthesis from N to C terminals. cyproheptadine.

CYPROHEPTADINE ANALOGUES, SAR FROM STRUCTURAL AND ELECTROSTATIC FITTINGS

J. Rodriguez,? E. Lozoya,? F. Manaut,? F. Sanz,l_ M.I. Loza,** M. Ho~bia,~~ M.I. Cadavid,** R. Dom~nguez,~ and M.C. Villaverde~ ?‘Institut Municipal d’lnvestigacio Medica, Facultat de Me- dicina (UAB), Barcelona, Spain *Dept. de Quimica Fisica, *Dept. de Quimica Organica, **Dept. de Farmacoloxia, Universidade de Santiago, Santiago de Compostela, Spain

The analogues of cyproheptadine shown in the Figure have been synthesized, and their activities as antagonists of sero- tonin-induced contractions in rat stomach fundus (5HT,, receptor) have been determined.

Cyprohep. 0

N

CH3

a, X=S b, X=0

bH,

% Cyprohep.

a

b

C

d

PA2 9.14

6.09

7.16

7.02

6.07

The geometries of the upper aromatic systems (the only fragment of the molecules that changes from one compound to another) have been optimized by ab initio calculations, and the molecular electrostatic potential (MEP) distributions have been computed. Structures and MEP distributions have been compared with those of cyproheptadine, looking for features related to the rank of activities. In the most active compounds (cyproheptadine, a and b) the tricyclic system gives rise to symmetrical “butterfly” conformations, which show a particular pattern of MEP negative zones. Activities

RIBBONS + +

M. Carson Center for Macromolecular Crystallography, University of Alabama at Bi~ingham, Bi~ingham, Alabama, USA

The IRIS Inventor is an object-oriented three-dimensional (3D) graphics tool kit developed by Silicon Graphics. This C + + programming environment provides a wide variety of geometric primitives, and methods for rendering them, in- cluding such advanced features as true transparency and texture mapping. These rendering features have been used to illustrate the following in the first two weeks we have had the software, by extending the Ribbons 2.0 program: molec- ular replacement solution of a protein structure, location of regions of potential coordinate error in the structure. and the results of the successful structure-based drug design of PNP inhibitors initiated in the laboratory. The more advanced 3D manipulation and event handling actions provided by the tool kit will be explored in the months leading up to the meeting. Potential applications include the refitting of a partially refined structure against the X-ray data, and the docking of inhibitors into an enzyme active site. The latest results will be presented.

EFFECTS OF VARIABLE SAMPLING ON CoMFA COEFFICIENT CONTOUR MAPS

G. Greco, E. Novellino, M. Pellecchia, C. Silipo, and A. Vittoria Dipartimento di Chimica Farmaceutica e Tossicologica, Universita degli Studi di Napoli, Napoles, Italy

We have recently investigated how CoMFA’ models may be affected by the removal of energy parameters by means of criteria different from the simple rejection of the variables associated with poor variance.

The data set chosen for our study comprises a subset of triazines of general formula 1, inhibiting dihydrofolate re- ductase (DHFR) from chicken liver. The considered data set, which was the object of an earlier paper by Hansch et al.,” appeared to us pa~icul~ly suitable for our purposes, since a QSAR model had already been developed and its consistency checked with the X-ray coordinates of ligand- enzyme complexes. The alignment rule and the bioactive conformations for the ligands were unambiguously defined,

In order to include the hydrophobicity of the substituents in the CoMFA models, the 7~ substituent constants for X3 and X4 were added to the CoMFA input data table through user-specified weighting factors.3

A standard CoMFA was first performed by sampling, for each structure, the steric and electrostatic fields before PLS analysis. A further CoMFA run was successively carried out

J. Mol. Graphics, 1994, Vol. 12, March 67