Kiralj R., Ferreira, M. M. C., “QSAR of  progestogens: Use of a priori and computer molecular descriptors and molecular graphics”.Copenhagen, Denmark, 19-23/08/2001: 7^th Scandinavian Symposium on Chemometrics (SSC7), Book of Abstracts, A10 (2001). Oral A10 in section: QSAR.

QSAR of progestogens: Use of a priori and
computed molecular descriptors and molecular
graphics

Rudolf Kiralj, rudolf@iqm.unicamp.br, Instituto de Química. UNICAMP, 13083-970, Brazil.
Márcia M. C. Ferreira, marcia@iqm.unicamp.br, Universidade Estadual de Campinas, Instituto de Química.
            Campinas, SP, 13083-970, Brazil

Keywords: progestogens, QSAR, molecular graphics

There are only a few recent attempts to describe progesterone and progestogens on a
quantitative level. Altough widely known as contraceptives, these compounds also showed to
be potential drugs for hormone and anti-cancer therapies, and for other clinical treatments,
what justifies studies of their molecular properties and intermolecular interactions with
various molecules. The lack of larger number and homogenicity of progestogens activity data
makes it difficult to have a clear picture of the progestogens behaviour at atomic level.
Recently, the one and only up to date crystal structure of progesterone-receptor complex¹
gave much insight into this intermolecular interaction.

Continuing the SAR idea² to relate molecular descriptors to contraceptive activity for two sets
of progestogens, we employed molecular graphics and QSAR analysis (Principal Component
Analysis and Partial Least Squares) here using both a priori³ and various computed
descriptors at a semi-empirical and an ab initio level. The smaller set of six progestogens
(derivaties of progesterone with changes of side chains at and of the bonds of the rings A, C,
and D) was successfully described by shape, sterical and electronic (as heteroatomaticity, etc.)
descriptors. The presence of hetero atoms and multiple bonds that can contribute to electron
delocalization via conjugation and hyperconjugation shows to be important for the
progestogene activity. The other set of progestogens, comprising nineteen progesterone
derivatives with small spherical substituents (mainly halogens, methyl and hydroxy group),
exhibits parabolical activity dependence on sterical parameters (size of substitutents) for each
substitution position.

Detailed analysis of the data will be disscussed. The a priori³ (simple hand or pocket
calculator made) descriptors will be compared with computed descriptors. The method of data
transformation for the nineteen progestogens to build a linear model will be presented.

References:
1. S. P. Williams, P. B. Sigler, Nature, 393 (1998) 392-396.
2. R. Vendrame, M. C. Ferreira, C. H. Collins, Y. Takahata, J. Mol. Graph., 19 (2001) in
press.
3. R. Kiralj, M. M. C. Ferreira, J. Mol. Graph., submitted for publication.
 
 
 

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