Drug hunting

Figures 11 and 12 illustrate the performance of the pR2 compared with several of the currently popular criteria on a specific data set resulting from one of the drug hunting projects at Eli Lilly. This data set has IC50 values for 1289 molecules. There were 2317 descriptors (or covariates) and a multiple linear regression model was used with forward variable selection the linear model was trained on half the data (selected at random) and evaluated on the other (hold-out) half. The root mean squared error of prediction (RMSE) for the test hold-out set is minimized when the model has 21 parameters. Figure 11 shows the model size chosen by several criteria applied to the training set in a forward selection for example, the pR2 chose 22 descriptors, the Bayesian Information Criterion chose 49, Leave One Out cross-validation chose 308, the adjusted R2 chose 435, and the Akaike Information Criterion chose 512 descriptors in the model. Although the pR2 criterion selected considerably fewer descriptors than the other methods, it had the best prediction performance. Also, only pR2 and BIC had better prediction on the test data set than the null model.

A. Pain killers best-sellers and H. Lipid lowering drugs hunting... 

Hubbard RL, Marsden ME, Rachal JV, et al Drug Abuse Treatment A National Study of Effectiveness. Chapel Hill, University of North Carolina Press, 1989 Hunt DE, Lipton DS, Goldsmith DS, et al It takes yom heart the image of methadone maintenance in the addict world and its effect on recruitment into treatment. Int J Addict 20 1751-1771, 1985-1986... 

Several studies have been performed in order to investigate the effect of liposomal size (Hirano and Hunt, 1985), lipid composition (Senior and Gregoriadis, 1982 Hirano et al., 1985), and lipid dose (Ellens et al., 1983, Kim et al., 1987) on the fate of liposomes after intraperitoneal administration. In the size range studied (0.048-0.72 Min), no size-dependent absorption could be expected (Hirano and Hunt, 1985). Particles larger than 22.5 pm are not expected to enter the lymphatic capillaries (Allen, 1956). After intraperitoneal administration of multivesicular liposomes (19 + 7 ym), Kim and Howell (1987a) and Kim et al. (1987) showed that liposomal entrapment of Ara-C prolongs the half-Ufe of the drug in the peritoneal... 

FIGURE 13 Schematic diagram for drug absorption fi om the peritoneal cavity. I and II represent the lymphatic system and III represents splenic blood capillaries. (Adapted from Hirano and Hunt, 1985.)... 

Hunt, C. A., Rustum, Y. M., Mayhew, E., and Papahadjopoulos, D. (1979). Retention of cytosine arabinoside in mouse lung following intravenous administration in liposomes of different size, Drug Metabol. Dispos., 7, 124-128. 

Very often, it is unknown which conformahon of a flexible molecule is needed. For example, in drug design, we hunt often for the so-called bioachve conformation, which is the molecule in its receptor-bound state. In this case, any other experimental structure of the isolated molecule - in vacuum, in soluhon or in crystal - can be the wrong choice. 

Jonkman, J. H. G. Hunt, C. A., Ion pair absorption of ionized drugs—fact or fiction ... 

JA Hunt, HN Joshi, VJ Stella, EM Topp. Diffusion and drug release in polymer films prepared from ester derivatives of hyaluronic acid. J Controlled Release 12 159-169, 1990. 

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