Molecular graphics-structural and molecular graphics descriptors in a QSAR study of 17-alpha-acetoxyprogesterones

Abstract

Neste trabalho, foi feito um estudo de relações quantitativas entre a estrutura e a atividade biológica de 21 derivados de progesteronas ministrados via oral, dentre os quais 19 são 17-αacetoxiprogesteronas. O método de quadrados mínimos parciais foi usado para construir modelos de regressão de boa qualidade, com Q 2 = 0,707 e R 2 = 0,811 utilizando duas componentes principais e quatro descritores. A maioria dos descritores moleculares foi obtida a partir de gráficos moleculares das geometrias otimizadas por meio de cálculos ab initio com um conjunto de base DFT 6-31G** (descritores moleculares gráficos). Os outros descritores foram obtidos pela combinação dos descritores anteriores com parâmetros estruturais experimentais extraídos do complexo progesteronareceptor da progesterona (descritores gráfico-estruturais ou descritores gráficos e de modelagem). Os modelos de regressão empregando somente cinco descritores gráficos e três componentes principais foram satisfatórios, Q 2 =0,556, R 2 =0,718, demonstrando a utilidade dos mesmos em estudos QSAR. Neste trabalho, onde foram estudados derivados de progesterona, ficou evidente que os descritores moleculares gráficos descreveram com sucesso os efeitos conformacionais, estéreos e eletrônicos dos diferentes substituintes.Quantitative Structure-Activity Relationship study on 21 oral progestogens, 19 of which are 17α-acetoxyprogesterones, was performed by using Partial Least Squares. Fairly good regression models were achieved, the best being Q 2 =0.707, R 2 =0.811 with two Principal Components and four descriptors. Most of the molecular descriptors were generated from molecular graphics of DFT 6-31G** optimized geometries (molecular graphics descriptors) or were additionally combined with experimental structural parameters of progesterone receptor -progesterone complex (molecular graphics-structural, or molecular graphics and modeling descriptors). Regression models employing only these molecular graphics-based descriptors reached Q 2 =0.556, R 2 =0.718 with three Principal Components and five descriptors, demonstrating their usefulness in QSAR studies. In the case of progesterone derivatives, molecular graphics descriptors successfully included various conformational, steric and electronic substituent effects.

Integral Sign Change Problem Check in Quantitative Structure-Activity/Property Relationships: A Tutorial

“…39 It was used to build a PLS model (model Id), 39 which was validated by certain methods. The original publication 39 contained descriptor pool (33 descriptors) and its subset related to model Id (15 descriptors). In this work, all the ISCP check levels were carried out, including the check levels 3a and 3b with 31 and 11 descriptors in the matrix X P , respectively.…”

Modeling the Interaction between Two- and Four-Ring Progestin Models and a Silicone-Based Polymer Model: A Density Functional Theory Study

“…8,9 DFT has recently been used to calculate the vibrational frequencies or structures of progesterone, 10,11 17R-hydroxyprogesterone, 12 desoxycorticosterone, 13,14 and a few other progesterone derivatives. 15 The ab initio and DFT method has also been applied to cation affinity studies of some neurosteroids, including progesterone. 16 Structural optimizations 17,18 and conformational stud-ies 19 of some progestins have been carried out by semiempirical calculations.…”

“…In this work, we use density functional theory (DFT) to investigate local interactions of four- and two-ring models of progesterone and those of its six hydroxyl derivatives with a dimethylsiloxane-based polymer modeling the drug delivery material. Ab initio theory has been previously applied to calculating the electronic structures of some progesterone molecules − and other steroids. , DFT has recently been used to calculate the vibrational frequencies or structures of progesterone, , 17α-hydroxyprogesterone, desoxycorticosterone, , and a few other progesterone derivatives . The ab initio and DFT method has also been applied to cation affinity studies of some neurosteroids, including progesterone .…”