3.5. Molecular docking with α-aminovalerophenone derivatives
The binding pocket can be divided into three subsites (A-C), (Figure 4A)
(Andersen et al., 2010; Cheng et al., 2015). As expected, the phenyl
ring was mainly located in subsite B (Saha et al., 2015), which
corresponds to an amphiphilic site where the phenyl group can interact
with Phe76 of TM1 helix through π-interaction. However, results
suggested a more stable configuration for α-PpVP (Figure 4F), in which
the phenyl group was oriented towards the hydrophobic subsite C.
Interestingly, the pyrrolidine group of α-PVP was subtly directed to
TM6, renouncing to interact with Asp79, amino-acid that interacts with
methamphetamine indeed (Figure 4B). This is in contrast to
N-ethyl-pentedrone (Figure 4C), pentedrone (Figure 4D) and
N,N-diethyl-pentedrone (Figure 4E), which showed similar binding
mechanism establishing an hydrogen bond between the amino group and
Asp79. The addition of an extra carbon atom in pentedrone seemed not to
affect the binding mechanism (Figure 4C-D) but the high hydrophobicity
of N,N-diethyl-pentedrone contrasted with the high polarity of subsite A
and modified its interaction mechanism (Figure 4E). Nevertheless, the
major change was observed in α-PpVP where the phenyl and propyl groups
exchange their orientations in comparison to α-PVP. It may be due to the
steric hindrance found by the piperidine substructure when attempting to
fit subsite A and the hydrophobic complementarity obtained when the
phenyl group is located within subsite C (Figure 4F). Predicted binding
affinities (approximated as docking score value) agreed with Kiexperimental data
(\(R_{\mathrm{\text{SCORE}}-\operatorname{}\left(\text{Ki}\right)}^{2}=0.93\))
and following the same order (Spearman correlation coefficient,