Drug-like compound

Computational approaches towards the rational design of drug-like compound libraries. Comb. Chem. High-Throughput Screen. 2001, 4, 453 75. 

Many excellent computer programs are available for predicting log P a from two-dimensional structures. The quality of predictions has risen over the years to the point that rouhne log P a measurements are not regularly done at some pharmaceutical companies, but rather, calculated values are used. It is worth noting that log Port values of newly synthesized classes of drug-like compounds sometimes are still poorly predicted and probably there will be the need for judicious log Port measurements for years to come. 

Interpretation of Measured Solubility of lonizable Drug-Like Compounds can be Difficult... 

Balakin, K., Savchuk, N., Tetko, I. In silica approaches to prediction of aqueous and DM SO solubility of drug-like compounds trends, problems and solutions. Curr. Med. Chem. 2006, 13, 223-241. 

Delaney [4,14] and Klamt [16] argued that for drug-like compound datasets only about 20% of the variance of log S arises from AG s. This is further confirmed by the study of Wassvik et al. [15] in which 77% of the variance is due to the solubility of the supercooled liquid. Hence, applying crude estimates by mean values or by QSAR approaches we can reasonably expect that the inaccuracies introduced in dmg solubility prediction by our theoretical ignorance of AG s is less than, or at least not much bigger than, the inaccuracies introduced by the estimates of the larger park i.e. the liquid solubility, and by the experimental difficulties in solubility measurement. 

QikProp does not perform MD simulahons but calculates required parameters from supplied 3D structures of molecules. For example, it computes atomic charges using the semi-empirical CM Ip method, ASA is calculated using a 1.4 A probe radius [43]. The recent parameters of QikProp were optimized using 500 drugs and related heterocyclic compounds and the model calculated an of 0.93 and an RMSE of 0.49 for more than 400 drug-like compounds [42]. 

Figure 7.55 shows a plot of over 2000 2%DOPC/dodecane Pe measurements (10-6 cm/s units), each representing at least three intra-plate replicates, vs. the estimated standard deviations, o(Pe). Over 200 different drug-like compounds were measured. The %CV (coefficient of variation 100 x a(Pe)/Pe) is about 10% near Pe 10 x 10 6 cm/s, and slightly increases for higher values of permeability, but rapidly increases for Pe< 0.1 x 10 6 cm/s, as shown in Table 7.21. These statistics accurately reflect the errors that should be expected in general. For some molecules, such as caffeine and metoprolol, %CV has been typically about 3-6%. 

We report here studies conducted with 58 crystalline drug-like compounds. The solubilities are of high quality, having been determined in only three laboratories using the same automated potentiometric method. However, the set is too small to... 

Palm and co-workers, as part of their research regarding the applicability of PSA, selected 20 compounds (Table 16.1) with quite reliable values for the percent fraction absorbed (%FA) in humans that were devoid of, or compensated for, problems such as active transport and efflux mechanisms [2]. The dataset consists of a variety of compounds drugs, drug-like compounds, as well as sugar-like structures. A number of studies based on this dataset using various structural descriptions have been performed [2, 17-22],... 

The aim of the present example was to investigate whether the assessment of an in silico model of metabolic stability from a training set of several hundred drugs or drug-like compounds in human CYP3A4 cDNA-expressed microsomal preparations, would offer a suitable approach to predict the metabolic stability of external compounds. 

Matter, H., Baringhaus, K. H., Naumann, T., Kiabunde, T., Pirard, B., Computational approaches towards the rational design of drug-like compound libraries, Comb. Chem. High Throughput Screen. 2001, 4, 453-475. 

There are minimal experimental data available for the R component of drug-like compounds. However, the quantification of the Rj component can be approximated using different methods or fragmental approaches. Fragments can be classified... 

A number of compounds with the lowest log BB values were overestimated by model 2. These entities were all drug-like compounds with a variety of structures and functional groups. Compounds at the other end of the scale, that is, compounds that exhibit high log BB values, are somewhat better predicted. These latter compounds were all hydrocarbons, for example, butanes, pentanes,... 

---