Drug-induced phospholipidosis (PLD) is an adaptive histologic alteration that is seen with various marketed drugs and often encountered during drug development. Various in silico and in vitro cell-based methods have been developed to predict the PLD-inducing potential of compounds. These methods rely on the inherent physicochemical properties of the molecule and, as such, tend to overpredict compounds as PLD inducers. Recognizing that the distribution of compounds into tissues or tissue accumulation is likely a key factor in PLD induction, in addition to key physicochemical properties, we developed a model to predict PLD in vivo using the measures of basicity (pK(a)), lipophilicity (ClogP), and volume of distribution (V(d)). Using sets of PLD inducers and noninducers, we demonstrate improved concordance with this method. Furthermore, we propose a screening paradigm that includes a combination of various methods to predict the in vivo PLD-inducing potential of compounds, which may be especially useful in lead identification and optimization processes in drug discovery.
The geometries and energies of beryllium clusters up to Be5 are examined using ab initio molecular orbital theory. Allowances are made for electron correlation with MBller-Plesset perturbation theory to fourth order. Correlation is found to have a dramatic effect on the relative energies of the several structures examined for Be4 and Bes. Furthermore, the effect of d-type basis functions on the correlation energy results in an increased binding energy for the clusters. Be2 is only weakly bound. For Be:i, the best estimate of the binding energy is 6 kcal/mole for the singlet equilateral triangle. Be4 is tetrahedral in its ground state and the estimated binding is 56 kcal/mole. The best structure for Be5 is a singlet trigonal bipyramid, and the binding energy is 88 kcal/mole at the highest level of theory used.
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