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Structure and function of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
These pharmacophore studies have demonstrated that typical CYP2D6 substrates are usually lipophilic bases with a planar hydrophobic aromatic ring and a nitrogen atom that can be protonated at physiological pH. These compounds usually have a negative molecular electrostatic potential above the planar part of the molecule. These features are typical of a large number of drugs acting on the central nervous and cardiovascular systems. The nitrogen atom is considered to be essential for electrostatic interactions with the carboxylate group of Asp301 or Glu216, two candidate residues in the active site of CYP2D6. These pharmacophore modeling studies suggest that substrate binding is generally followed by oxidation 5 to 7 Å from the proposed nitrogen–Asp301/Glu216 interaction. Lipophilicity and amine basicity are thus considered to be important determinants of substrate/inhibitor binding to CYP2D6. LogP has been correlated to the inhibition constant (Ki or log Ki) for a series of β-blockers for CYP2D6 (Ferrari et al. 1991) and there is an inverse relationship between logP and inhibitory potency of quinidine metabolites for CYP2D6 (Ching et al. 1995). Quinidine and dihydroquinidine are potent CYP2D6 inhibitors with Ki values of 0.027 and 0.013 μM, respectively, while 3-hydroxyquinidine, O-desmethylquinidine, and quinidine N-oxide inhibit this enzyme with higher Ki values (0.43 to 2.3 μM) (Ching et al. 1995). The improved pharmacophore models have been used to rationalize and predict many CYP2D6-catalyzed reactions.
Fluorinated scaffolds for antimalarial drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Charu Upadhyay, Monika Chaudhary, Ronaldo N. De Oliveira, Aniko Borbas, Prakasha Kempaiah, Poonam S, Brijesh Rathi
Quinine is an old anti-malarial drug that originated from the bark of cinchona tree [82]. The ability of quinine to inhibit bio-mineralization of hemozoin shows its potency against the malaria parasite [83]. Bucher, C. and coauthors have synthesized a chemical library of selectively fluorinated quinine scaffolds [84]. Twenty novel fluorinated quinine alkaloid compounds were screened against the PfNF54 strain of the malaria parasite using 3 H-hypoxanthine assay. According to the summarized activity data, it was identified that the presence of the azabicyclo[2.2.2] core is critical for drug efficacy. Replacing the quinuclidine moiety with the ring-expanded [3.2.2]-bicyclic moiety showed a major loss in antimalarial activity, as noted for the hydroquinidine analogue 68 (IC50 = 9530 nM).
Precision medicine in cardiac electrophysiology: where we are and where we need to go
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ashish Correa, Syed Waqas Haider, Wilbert S. Aronow
In SQTS, the underlying molecular aberration is gain-of-function mutations in genes encoding the membrane-bound potassium channels resulting in rapid repolarization and short QT intervals. Recognizing this pathophysiology, various anti-arrhythmics which prolong the QT interval and thus could potentially normalize QT interval in SQTS were tested. Hydroquinidine was the only agent found to be effective in prolonging the QT interval [106]. It has since been found to be beneficial in SQTS patients, particularly in those with gain-of-function KCNH2 mutations [107,108]. Thus, quinidine now can be used both for intensification of therapy in patients experiencing ICD shocks and for asymptomatic patients or in symptomatic patients who do not get ICDs due to contraindications or refusal [59].
Pharmacotherapy in inherited and acquired ventricular arrhythmia in structurally normal adult hearts
Published in Expert Opinion on Pharmacotherapy, 2019
Staniel Ortmans, Charline Daval, Martin Aguilar, Pablo Compagno, Julia Cadrin-Tourigny, Katia Dyrda, Lena Rivard, Rafik Tadros
Quinidine is an Ito current inhibitor and the oral antiarrhythmic drug of choice in patients with BrS to prevent and terminate VA, electrical storm and frequent ICD shocks in BrS patients [12,13]. In a cohort of 96 BrS patients, Belhassen et al. showed that quinidine was able to prevent VF induction in 89.6% (52/58) of patients tested by an aggressive stimulation protocol with an overall annual arrhythmic event-rate of 1% during a median follow-up of 113 months. Moreover, the QUIDAM study published in 2017 was a prospective multicenter randomized double-blinded study comparing hydroquinidine to placebo with two 18-months crossover phases in 50 high-risk patients with BrS and implanted with an ICD. During the 36-month follow-up period, two arrhythmic events occurred under placebo (1 appropriate ICD shock, 1 self-terminating ventricular fibrillation and 1 inappropriate shock) and no arrhythmic events were reported under hydroquinidine therapy [14]. In the same way, Hermida et al. showed that hydroquinidine therapy prevented VT/VF inducibility in 76% of asymptomatic patients with BrS and inducible arrhythmia [15].