Figure 2 . Elimination score (SE) for the most
promising rasagiline derivatives, according to SS.
Columns are divided to show the influence of the new contributions
included in each score, with respect to the previous one.
Figure 2 shows that the new properties included in
SE,ADME8, and the toxicity indexes have the largest
contribution to SE,ADMETSA. Thus, the proposed index
emphasizes the importance of toxicity in the choice of candidates drugs.
Figure 3 shows a more meticulous analysis of the individual
contributions of the different parameters to the
SE,ADMETSA elimination score.
The largest deviations arise mainly from LD50, M, PSA,
MW, HBA, and HBD.
Regarding LD50, the rasagiline derivatives deviating the
most from the average value (R-8, RI-36 and
RII-2) are less toxic to rats than the reference
compounds (LD50 = 960.8)140-142. Their
LD50 were estimated to be 1970.2, 1613.9, 1882.0, and
2644.1, respectively. Thus, these important deviations imply a more
desirable behaviour, compared to the reference set. Therefore, these
derivatives were included in the subset selected as the most promising,
based on ADMETSA properties. A similar trend was found for the Ames
mutagenicity, i.e., the compounds predicted as the least mutagenic are
just those that deviate the most from the reference set (M =
0.41)140-142. They are RI,
RI-4, RI-36, RI-49,
RI-97, RII-2, and RII-10
all with M ≤ 0.03. Consequently, it is essential not only to detect the
designed molecules with the largest deviation from the reference set,
but also to examine what causes such deviations. Otherwise, promising
candidates could be excluded for no good reason.