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Cytochrome P450 Enzymes for the Synthesis of Novel and Known Drugs and Drug Metabolites
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sanjana Haque, Yuqing Gong, Sunitha Kodidela, Mohammad A. Rahman, Sabina Ranjit, Santosh Kumar
Engineered CYPBM3 can be used to improve the biocatalytic oxidation, producing valuable industrial chemicals (Wang et al., 2014; Dezvarei et al., 2018a), while wild-type enzymes only catalyze small amount of industrially relevant chemicals (Huisman and Collier, 2013). For example, an engineered CYPBM3 was able to synthesize the chemical core of levomilnacipran, which can be used to treat depression clinically. This engineered enzyme, BM3-Hstar, was able to catalyze the cyclopropanation of N,N-diethyl-2-phenylacrylamide with 1000 turnovers per minute and can be used under aerobic conditions, while wild-type BM3 has very low cyclopropanation activity. Compared with the traditional transition metal catalytic approaches, the enzymatic method is more attractive because of its stereo-selective and non-toxic profile. Importantly, BM3-Hstar was able to provide the desired product at 92% yield with 92% enantioselectivity and 2:98 diastereoselectivity (Wang et al., 2014). Another report has also shown the enhanced cyclopentane and cyclohexane oxidation by an engineered CYPBM3 with decoy molecules. This engineered CYPBM3 was able to oxidize cycloalkanes up to 8000-fold higher than the wild-type enzyme, at product formation rates up to 1700 nmol·nmol-CYP−1·min−1 (Dezvarei et al., 2018a). Moreover, engineered CYPBM3 mutants can be used as biocatalysts to overcome the challenge on selective C-H oxidation of terpenoid scaffolds. Several CYPBM3 variants generated from direct evolution were used to catalyze tobacco cembranoid β-cembrenediol. The F87A/I263L mutant and the L75A/V78A/F87G mutant were able to hydroxylate the neighboring positions C-9 (100% regioselectivity, diastereomeric ratio of 89:11) and C-10 (97% regioselectivity, diastereomeric ratio of 74:26) of β-cembrenediol. Since no chemical synthesis is available to perform this late-stage C-H oxyfunctionlization, this study showed the importance of engineered CYPBM3 as a biocatalyst in chemoenzymatic synthesis of larger complex molecules (Le-Huu et al., 2015).
Chirality and neuropsychiatric drugs: an update on stereoselective disposition and clinical pharmacokinetics of bupropion
Published in Xenobiotica, 2018
Ranjeet Prasad Dash, Rana Rais, Nuggehally R. Srinivas
From an introspection perspective, it is important to ask the question: would answering such questions related to stereoselective disposition and understanding of drug–drug interaction potential of bupropion change the safety/efficacy aspects of bupropion in clinical therapy? While no doubt the approved use of bupropion has been found to be safe, the relevance of understanding of stereoselective drug–drug interaction potential of bupropion cannot be discounted given the polypharmacy that currently exists in treating various diseases including CNS indications. Additionally, with increased scrutiny on the implications of chirality in clinical drug therapy, the current data may provide an impetus for clinical evaluation of individual bupropion enantiomers. In this context, better safety and improved efficacy were key considerations to the recent US approval of levomilnacipran (a levo isomer of milnacipran) in treating psychiatric patients (Zadka et al., 2016). Previously, notable examples of single enantiomer marketing authorisations in the CNS area include: escitalopram (S-enantiomer of racemic citalopram), eszopiclone (S-enantiomer of racemic zopiclone) and dexmethylphenidate (d-enantiomer of racemic methylphenidate) demonstrating the importance of chirality for drug approvals in treating patients with different psychiatry disorders such as major depression, insomnia and attention-deficit disorder etc. (McGough et al., 2005; Melton et al., 2005; Pastoor & Gobburu, 2014).