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N.Gorinchoy et al./Chem.J.Mold. 2008, 3 (1), 94-10421Cl10.347Cl3C5Cl25.3040.3403.9561.0980.2963.0603.0532.6630.34222Cl10.341Cl3C5Cl25.2950.3403.9561.1070.3023.0483.0442.6630.34124C30.365C8C9C64.7260.3494.4070.9620.3513.0502.5223.0590.35525C80.369C3C2C54.7160.3494.3880.9630.3613.0502.5223.0600.355Averaging the corresponding matrix elements in these 17 sub-matrices we obtained the following averagedmatrix of toxicity Tˆav :T10.3954.803 4.053 3.053ˆT 20.350 1.207 2.743T av(3)T30.302 2.481T 40.318with the matrix of tolerances (in relative values of the matrix elements):0.1620.105 0.144 0.131ˆ 0.133 0.202 0.121T 0.160 0.233(4)0.116 relresulting in following ECSA, the digital toxicophore for the 17 compounds with the toxicity in interval-1.32 < -log LC 50< 0.30:0.395 0.064 4.803 0.504 4.053 0.585 3.053 0.4010.350 0.046 1.207 0.244 2.743 0.332T 0.302 0.049 2.4810.578(5)0.318 0.037 99
N.Gorinchoy et al./Chem.J.Mold. 2008, 3 (1), 94-104Moving to the compounds with lower activity one may find out that this ECSA (revealed for the most activecompounds) does not work for them, but they can be accommodated within this ECSA by allowing larger tolerances. Inthis way one can get slightly different ECSA’s and hence pharmacophores/toxicophores for different levels of activity.The activity is thus quantitatively a function of the tolerances. The dynamics of change of the tolerances of differentatoms when moving from more active to less active compounds reveals also the role of their flexibility in the changeof activity.Let us illustrate this important feature by an example. The compound benzaldehyde with logLC 50= 1.57 has thefollowing ECSA: O10.51 4.79 5.06 2.89C30.35 1.45 2.79(6)C40.31 2.41C60.31We see that although this matrix does not fit to the above ECSA for the most active compounds (5), it fails justby some increase of the tolerances, mainly in the distance 5.06 between the oxygen atom and the carbon C4, whichis out of the limits of the corresponding distance 4.05±0.58 in the most active compounds. This feature comprises thenext 7 less active compounds with toxicities 1.9 > logLC 50>1.4. It demonstrates the important role of the most activeheteroatom (chlorine, oxygen, etc.) in the toxicity. The falling toxicity with the increase of the distance of this activeatom to the main skeleton of the molecule may be due to either its out of the limits of efficient docking to the bioreceptoror its poor bonding and hence decay through the metabolic processes. The dependence of the quantitative activity on thetolerances is of general importance in the EC method, and it is used to estimate the activity quantitatively (see below).As mentioned above, this picture of activity presented by ECSA as the pharmacophore or toxicophore and thedependence of the quantitative activity on the tolerances may be complicated by the presence of out-of-pharmacophoregroups that influence the activity either by shielding of or competing with the pharmacophore in its interaction withthe bioreceptor [8]. Therefore the presence of the pharmacophore should be considered as just a necessary condition ofactivity, but not a sufficient one. Since it is based on first principles (quantum-chemical calculations) and not involvingstatistics, the prediction of the pharmacophore in the EC method has a potential of the same reliability as that of theexperimental data of the training set, meaning 100% reliability if based on experimental data of highest accuracy. Thelatter are thus most important in getting the absolutely reliable pharmacophore.Another important feature that influences the pharmacophore in the EC method is the diversity of the trainingset. The ECSA (the pharmacophore/ toxicophore) is valid for levels of activity and classes of molecules the ECMCof which were used in its calculation. For the same mechanism of substrate-receptor interaction different classes ofcompounds should have the same pharmacophore, but if the latter is obtained from one (or a limited number) of classeswith active compounds, it may happen that it includes more active sites (atoms) than the minimal necessary, which thusmay be absent in active molecules from other classes.To screen new compounds for the activity under consideration, their ECMC should be calculated, and then thepresence of the ECSA should be checked taking into account the above class and activity level limits. If only very activecompounds are looked for, the ECSA (5) of the highly active ones should be tried, while for less active compoundsanother ECSA (with enlarged tolerances) should be involved. We thus have a very flexible system of searching for leadsof active compounds. Presently these procedures of matrix comparison are very fast.The high reliability of pharmacophore identification by the EC method may serve as a basis for revealing novelknowledge [7]. Indeed, if the pharmacophore is a necessary condition of activity, it should be present in all the activecompounds. What if there are active compounds that have no pharmacophore (as in some of the above compounds inTable 1)? If the structure of the molecules, as well as the experimental measurement of activity are beyond doubt and thecompound under consideration is within the diversity of the training set, the situation calls for a special investigation.The first time we encountered such a case was in the search for the pharmacophore in musk odorant activity [24]. Thepharmacophore that was present in several hundred compounds with musk odor from a variety of rather different classesfailed in the case of a patented musk tibeten (a benzene derivative). The solution of this controversy was found in thesuggestion that this molecule exhibits its odor properties in the form of a dimer formed by two stacking substitutedbenzene rings; the dimer has the pharmacophore.In fact bimolecular activity does not require a priori dimerization before the interaction with the bioreceptor.Indeed, it is widely accepted that the drug-receptor interaction, like any other substrate(S)-enzyme(E) interaction,follows the Michaelis-Menten mechanism [25] with pre-equilibrium in the formation of the complex SE before thetransformation to the product P:S + E SE P (7)100
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