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Series: De Gruyter STEM
Heritage Sciences
Applications, Synthesis and In-Situ Characterization
From Theory to Research
Series: De Gruyter STEM

Abstract

In this chapter mono, di, tri and tetraaza substituted phenanthrene derivatives have been investigated computationally with B3LYP/6-31 + G(d,p) level of theory. Substitution of carbon atom of the main structure with nitrogen obviously disturbs the aromaticity, indeed it decreases it. Thus, the idea of regaining of the aromaticity back by using electron withdrawing groups came across. As a result of the computational calculations, energetically most unfavored structures have been found to be those where aza substitutiona are vicinal. Secondly, the aromaticities of the present species depend on the position of the centric substituent. In addition, the effect position of the side substituent has been considered. The system becomes more aromatic (possess greater negative NICS values or smaller HOMA value) when the electron withdrawing atoms or groups are adjacent to the centrically substituted heteroatoms.

Abstract

Methadone is a morphine-substitute drug in methadone maintenance treatment (MMT) program to treat patients with opioid dependency. However, the methadone clinical effects are depending on the methadone metabolism rates that vary among the patients with genetic polymorphism of cytochrome P450s (CYPs). Our previous study showed methadone has different binding affinity due to the polymorphisms in CYP2B6, CYP2D6 and CYP3A4 that could contribute to the methadone metabolism rate. In this work, the conformation and interactions of R- and S-methadone in wild type CYP2B6, CYP2D6 and CYP3A4 were further studied in order to understand behaviour of R- and S-methadone at the CYP binding site. Clustering analysis showed that the conformation of R- and S-methadone in CYP2B6 are most stable, thus could lead to a higher efficiency of methadone metabolism. The conformation fluctuation of methadone in CYP2D6 could due to relatively smaller binding pocket compared with CYP2B6 and CYP3A4. The binding sites volumes of the studied CYPs were also found to be increased upon the binding with methadone. Therefore, this might contributed to the interactions of both Rand S-methadone in CYPs were mainly by hydrophobic contacts, van der Waals and electrostatic interactions. In the future, should an inhibitor for CYP is to be designed to prolong the prolonged opioid effect, the inhibitor should cater for single CYP isozyme as this study observed the behavioural differences of methadone in CYP isozymes.