Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors

Summary Inhibition of aromatase, a cytochrome P450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quantitative structure-activity relationship (3D QSAR) method known as Comparative Molecular Field Analysis, CoMFA [Cramer III, R.D. et al., J. Am. Chem. Soc., 110 (1988) 5959]. We analyzed the data for 50 steroid inhibitors [Numazawa, M. et al., J. Med. Chem., 37 (1994) 2198, and references cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(1/K_i), with an explained variance r² of 0.885, and a cross-validated q² of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12 (1993) 9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compounds (repeated 25 times), the q² for one component was 0.62 and 0.61, respectively, while r² was 0.674. We demonstrate that the predictive r² based on the mean activity (Y_m) of the training set is misleading, while the test set Y_m-based predictive r² index gives a more accurate estimate of external predictivity. Using CoMFA, the observed differences in aromatase inhibition among C6-substituted steroids are rationalized at the atomic level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compounds have distinct features that overlap with the steric and electrostatic fields obtained in the CoMFA model. The presence of two hydrophobic binding pockets near the aromatase active site is discussed: a steric bulk tolerant one, common for C4, C6-alpha and C7-alpha substitutents, and a smaller one at the C6-beta region.     

Optimal control for semilinear stochastic evolution equations

Existence, uniqueness, continuous dependence with respect to controls and convergence in the probability of finite differences for controlled semilinear stochastic evolution equations, driven by continuous semimartingales, are considered under Lipschitz and monotone coefficients. The existence of discrete-optimal feedback controls for an associated optimization problem is proved.     

Asymptotic expansion for vector-valued sequences of random variables with focus on Wiener chaos

We develop the asymptotic expansion theory for vector-valued sequences ${\left(F_N\right)}_{N\ge 1}$ of random variables in terms of the convergence of the Stein–Malliavin matrix associated with the sequence $F_N$. Our approach combines the classical Fourier approach and the recent Stein–Malliavin theory. We find the second order term of the asymptotic expansion of the density of $F_N$ and we illustrate our results by several examples.     

SPDE with generalized drift and fractional-type noise

We consider a stochastic partial differential equation involving a second order differential operator whose drift is discontinuous. The equation is driven by a Gaussian noise which behaves as a Wiener process in space and the time covariance generates a signed measure. This class includes the Brownian motion, fractional Brownian motion and other related processes. We give a necessary and sufficient condition for the existence of the solution and we study the path regularity of this solution.     

On the Equivalence of Multiparameter Gaussian Processes

Our purpose is to characterize the multiparameter Gaussian processes, that is Gaussian sheets, that are equivalent in law to the Brownian sheet and to the fractional Brownian sheet. We survey multiparameter analogues of the Hitsuda, Girsanov and Shepp representations. As an application, we study a special type of stochastic equation with linear noise.      

Invariant generators for generalized distributions

The existence of invariant generators for distributions satisfying a compatibility condition with the symmetry algebra is proved.     

Acute Triangulations of the Regular Icosahedral Surface

We prove here that the surface of the regular icosahedron can be triangulated with 8 non-obtuse and with 12 acute triangles. We also show these numbers to be smallest possible.     

On Planar Toeplitz Graphs

We describe several classes of finite, planar Toeplitz graphs and present results on their chromatic number. We then turn to counting maximal independent sets in these graphs and determine recurrence equations and generating functions for some special cases.