Integration of ligand and structure-based virtual screening for identification of leading anabolic steroids.

Parallel ligand- and structure-based virtual screenings of 269 steroids with anabolic activity evaluated in vivo were performed. The quantitative structure-activity relationship (QSAR) model expressed by selected descriptors as the octanol-water partition coefficient, the molar volume and the quantum mechanical calculated charge values on atoms C1, C2, C5, C9, C10, C14 and C17 of the steroid skeleton, expresses structural features of anabolic steroids (AS) contributing to the transport and steroid-receptor interaction. On the other hand, computational simulations of a candidate ligand binding to a receptor study (a "docking" procedure) predict the association of these AS with the human androgen receptor (AR). Fourteen compounds were identified as lead; the most potent was the 7α-methylestr-4-en-3, 17-dione. It was concluded that a good anabolic activity requires hydrogen bonding interactions between both Arg752 and Gln711 residues in the cycles A with O3 atom of the steroid and either Asn705 and Thr877 residues in the cycles D of steroid with O17 atom.

Anabolic and androgenic activities of 19-nor-testosterone steroids: QSAR study using quantum and physicochemical molecular descriptors.

Quantitative structure-activity relationship (QSAR) study of 19-nor-testosterone steroids family was performed using quantum and physicochemical molecular descriptors. The quantum-chemical descriptors were calculated using semiempirical calculations. The descriptor values were statistically correlated using multi-linear regression analysis. The QSAR study indicated that the electronic properties of these derivatives have significant relationship with observed biological activities. The found QSAR equations explain that the energy difference between the LUMO and HOMO, the total dipole moment, the chemical potential and the value of the net charge of different carbon atoms in the steroid nucleus showed key interaction of these steroids with their anabolic-androgenic receptor binding site. The calculated values predict that the 17α-cyclopropyl-17ß, 3ß-hydroxy-4-estrene compound presents the highest anabolic-androgenic ratio (AAR) and the 7α-methyl-17ß-acetoxy-estr-4-en-3-one compound the lowest AAR. This study might be helpful in the future successful identification of "real" or "virtual" anabolic-androgenic steroids.

Chemometric and chemoinformatic analyses of anabolic and androgenic activities of testosterone and dihydrotestosterone analogues.

Predictive quantitative structure-activity relationship (QSAR) models of anabolic and androgenic activities for the testosterone and dihydrotestosterone steroid analogues were obtained by means of multiple linear regression using quantum and physicochemical molecular descriptors (MD) as well as a genetic algorithm for the selection of the best subset of variables. Quantitative models found for describing the anabolic (androgenic) activity are significant from a statistical point of view: R(2) of 0.84 (0.72 and 0.70). A leave-one-out cross-validation procedure revealed that the regression models had a fairly good predictability [q(2) of 0.80 (0.60 and 0.59)]. In addition, other QSAR models were developed to predict anabolic/androgenic (A/A) ratios and the best regression equation explains 68% of the variance for the experimental values of AA ratio and has a rather adequate q(2) of 0.51. External validation, by using test sets, was also used in each experiment in order to evaluate the predictive power of the obtained models. The result shows that these QSARs have quite good predictive abilities (R(2) of 0.90, 0.72 (0.55), and 0.53) for anabolic activity, androgenic activity, and A/A ratios, respectively. Last, a Williams plot was used in order to define the domain of applicability of the models as a squared area within +/-2 band for residuals and a leverage threshold of h=0.16. No apparent outliers were detected and the models can be used with high accuracy in this applicability domain. MDs included in our QSAR models allow the structural interpretation of the biological process, evidencing the main role of the shape of molecules, hydrophobicity, and electronic properties. Attempts were made to include lipophilicity (octanol-water partition coefficient (logP)) and electronic (hardness (eta)) values of the whole molecules in the multivariate relations. It was found from the study that the logP of molecules has positive contribution to the anabolic and androgenic activities and high values of eta produce unfavorable effects. The found MDs can also be efficiently used in similarity studies based on cluster analysis. Our model for the anabolic/androgenic ratio (expressed by weight of levator ani muscle, LA, and seminal vesicle, SV, in mice) predicts that the 2-aminomethylene-17alpha-methyl-17beta-hydroxy-5alpha-androstan-3-one (43) compound is the most potent anabolic steroid, and the 17alpha-methyl-2beta,17beta-dihydroxy-5alpha-androstane (31) compound is the least potent one of this series. The approach described in this report is an alternative for the discovery and optimization of leading anabolic compounds among steroids and analogues. It also gives an important role to electron exchange terms of molecular interactions to this kind of steroid activity.

Applying pattern recognition methods plus quantum and physico-chemical molecular descriptors to analyze the anabolic activity of structurally diverse steroids.

The great cost associated with the development of new anabolic-androgenic steroid (AASs) makes necessary the development of computational methods that shorten the drug discovery pipeline. Toward this end, quantum, and physicochemical molecular descriptors, plus linear discriminant analysis (LDA) were used to analyze the anabolic/androgenic activity of structurally diverse steroids and to discover novel AASs, as well as also to give a structural interpretation of their anabolic-androgenic ratio (AAR). The obtained models are able to correctly classify 91.67% (86.27%) of the AASs in the training (test) sets, respectively. The results of predictions on the 10% full-out cross-validation test also evidence the robustness of the obtained model. Moreover, these classification functions are applied to an "in house" library of chemicals, to find novel AASs. Two new AASs are synthesized and tested for in vivo activity. Although both AASs are less active than some commercially AASs, this result leaves a door open to a virtual variational study of the structure of the two compounds, to improve their biological activity. The LDA-assisted QSAR models presented here, could significantly reduce the number of synthesized and tested AASs, as well as could increase the chance of finding new chemical entities with higher AAR.

Escalado industrial del proceso de obtención de diosgenina acetato / Climbed industrial of the process of obtaining of diosgenine acetate

Se realizó un estudio a nivel de laboratorio y se evaluó la influencia de la temperatura de adición de la Diosgenina con vistas a su transformación en Diosgenina acetato, así como se ajustaron parámetros de centrifugación y lavado que nos permitieron escalar a un nivel industrial con resultados satisfactorios. Se evaluó la calidad del residual de reacción y su posible recuperación con vistas a su reutilización o comercialización a otra entidad como ácido acético (AU)

Oxidación de metilandrostanodiol con hipoclorito de sodio / Metilandrostanodiol oxidation with hipoclorito of sodium

Se emplea hipoclorito de sodio de producción nacional como agente oxidante y se utiliza como método de trabajo un diseño fraccionario de 25-1 y como variable dependiente un criterio de ocupación integral, que agrupa el rendimiento y los parámetros de calidad del producto de la reacción. Con estos resultados se logra simplificar dicho procedimiento, empleado en la síntesis de oximetolona a partir de hecogenina(AU)

Oxidación de metilandrostanodiol con hipoclorito de sodio

Se emplea hipoclorito de sodio de producción nacional como agente oxidante y se utiliza como método de trabajo un diseño fraccionario de 25-1 y como variable dependiente un criterio de ocupación integral, que agrupa el rendimiento y los parámetros de calidad del producto de la reacción. Con estos resultados se logra simplificar dicho procedimiento, empleado en la síntesis de oximetolona a partir de hecogenina.

Oxidación de metilandrostanodiol con hipoclorito de sodio / Methyl-androstanediol oxidation with sodium hypochlorite

Se emplea hipoclorito de sodio de producción nacional como agente oxidante y se utiliza como método de trabajo un diseño fraccionario de 2ü y como variable dependiente un criterio de ocupación integral, que agrupa el rendimiento y los parámetros de calidad del producto de la reacción. Con estos resultados se logra simplificar dicho procedimiento, empleado en la síntesis de oximetolona a partir de hecogenina (AU)

Transposición del grupo carbonilo en la hecogenina / Transposition of the carbonyl group in hecogenine

La hecogenina es una sapogenina esteroidal que se emplea industrialmente en la síntesis de corticosteroides. La acción antiinflamatoria deestos medicamentos depende, en gran medida, de la presencia oxigenada en el car bono 11 del esqueleto esteroidal. La hecogenina presenta un grupo carbonilo en la posición 12 de la molécula y su transformación en corticosteroides requiere entre otras reacciones, la transposición de esta función a la posición 11. En elpresente trabajo se describe una nueva vía de obtensión del 3 beta, 12 beta-dihidroxi-11-ceto-espirostano(cetol), intermediario en la síntesis de corticosteroides a partir de hecogenina. Los productos sintetizados se identificaron por sus características físicas y espectrocópicas

Transposición del grupo carbonilo en la hecogenina / Transposition of the carbonyl group in hecogenine

La hecogenina es una sapogenina esteroidal que se emplea industrialmente en la síntesis de corticosteroides. La acción antiinflamatoria deestos medicamentos depende, en gran medida, de la presencia oxigenada en el car bono 11 del esqueleto esteroidal. La hecogenina presenta un grupo carbonilo en la posición 12 de la molécula y su transformación en corticosteroides requiere entre otras reacciones, la transposición de esta función a la posición 11. En elpresente trabajo se describe una nueva vía de obtensión del 3 beta, 12 beta-dihidroxi-11-ceto-espirostano(cetol), intermediario en la síntesis de corticosteroides a partir de hecogenina. Los productos sintetizados se identificaron por sus características físicas y espectrocópicas