## 3 Biotransformation of Viniferins
### Prediction of Some Parameters That Describe Drug-Likeness
#### 5.2.3. Predicted Pharmacokine Properties of Chosen Viniferins and Vniferin-Based Compounds
Polymorphic CYP2C19 isoform biotransforms numerous drugs belonging to various PD classes and is responsible for differences in their PK properties that lead to the formation of pharmacologically active or inactive metabolites [210]. Many different pharmacophore models for effective CYP2C19 inhibitors and substrates have been proposed and more or less extensively described. In that regard, review papers [211,212] can be mentioned as suitable examples. Higher structural flexibility of the compounds in the current study contributed to more effective in silico inhibition of CYP2C19 (\(r\) = 0.753). The significance of lipophilicity, described with the outputs of particular computational methods, was lower. In addition, decreased \(tPSA\) values of the molecules (**16**)-(**29**) were partially favorable (\(r\) = \(-\)0.655) for the inhibition of CYPC19 (Table S6). The CYP2C9 isoenzyme is also notably involved in particular biotransformation pathways in humans [213]. The presence and proper position of single bonds within the structure of the evaluated molecules, i.e., increased flexibility, was convenient for their CYP2C9 inhibitory activity (\(r\) = 0.746). The increase in \(MW\) (\(r\) = 0.518) or \(V_{\text{vdv}}\) (\(r\) = 0.527) was less significant for such a predicted biological property (Table S6). The compounds (**24**) and (**26**)-(**28**) were computationally indicated as the most powerful CYP2C9 inhibitors (Table S5). Higher lipophilicity, connected with a higher count of aromatic systems, slightly favored these derivatives as the CYP2C9 inhibitors compared to their CYP2C19 inhibitory efficiency (Table S5). None of the calculated structural or physicochemical descriptors were significantly positively or negatively connected with the capability of the molecules (**16**)-(**29**) to serve as suitable CYP2C9 substrates (\(\,|\,r\,|<\) 0.390; Table S6). Another polymorphic CYP2D6 isoenzyme also participates in the biotransformation of drugs from various PD groups, for example, antihypertensive agents, antidysrhythmics, antipsychotic drugs, antidepressants belonging to different subclasses, or analgesics [214]. The highest potential to inhibit CYP2D6 was calculated for (**22**)-(**24**) containing a modified hydrocarbon chain. In general, the lipophilicity predicted for physiological conditions (log \(D_{7.4}\)) positively contributed to the increase in this inhibitory property to a relatively notable extent (\(r\) = 0.668). The center(s) of protonation that would be ionized at a physiological p\(H\) value, i.e., basic \(N\)-atom(s), should be present in a structure of suitable CYP2D6 substrates [215]. The majority of analyzed compounds **(16)-(29)** might be prospective CYP2D6 substrates, excluding **(16)**, **(17)**, and **(28)**, despite the fact that this structural requirement was missing (Table S5). It might be assumed that aromatic moieties, lipophilic atoms, and hydrogen-bond acceptor groups were sufficient for noncovalent interactions with particular amino acid residues within CYP2D6 to form the required hydrophobic and \(\pi\)-\(\pi\) interactions, as well as hydrogen bonds. This proposal was in agreement with conclusions published in [212]. The lipophilic properties predicted via WLOGP (\(r=0.503\)) and log \(D_{7.4}\) (\(r=0.453\)) only partially positively contributed to the ability of evaluated compounds to serve as the substrates for CYP2D6. Polymorphic CYP2B6 isoenzyme also contributes to the biotransformation of various drugs belonging to antidepressants, analgesics, antiviral agents, or anticancer compounds [216]. The structural flexibility of the investigated compounds was partially beneficial (\(r=0.510\)) for the increased potential to be effective CYP2B6 inhibitors. The increase in lipophilicity, expressed with log \(D_{7.4}\) (\(r=-0.817\)), relatively notably decreased this capability. Moreover, the increased \(tPSA\) parameters also partially reduced this property (\(r=-0.407\); Table S6).