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,