Molecular Modeling of Chiral Drugs
Background:
About more than half of the over the counter and prescription drugs are chiral compounds but almost 90% of them are sold as racemates consisting of a 50:50% mixture of two enantiomers (Nguyen, et. al., 2006). As learned in this Module, although enantiomers have the same chemical structure, many chiral drugs have differences in biological activities such as pharmacology, toxicology, pharmacokinetics, and metabolism. For example, Advil contains S-ibuprofen that is over 100-fold more potent as an inhibitor of cyclooxygenase I than (R)-ibuprofen. Furthermore, in the body, only inactive R-enantiomer inverts by hepatic enzymes into the active S-enantiomer (Landoni, 2001 and Marzo, 2002).
Instructions:
Pick one molecules of the following racemic drugs with one major bioactive enantiomer
Calcium channel antagonists are used under racemic form such as verapamil, nicardipine, nimodipine, nisoldipine, felodipine, mandipine.
Angiotensin-converting enzyme (ACE) inhibitors are medications that help relax the veins and arteries to lower blood pressure. ACE inhibitors include captopril, benazepril, enalapril, idapril.
Hypnotics such as hexobarbital, secobarbital, mephobarbital, pentobarbital, thiopental, thiohexital.
Racemic drugs with equally bioactive enantiomers, such as cyclophosphamide (antineoplastic), flecainide (antiarrhythmic), fluoxetine (antidepressant).
Nonsteroidal anti-inflammatory drugs (NSAID), namely ibuprofen, ketoprofen, fenprofen, benoxaprophen,
Conduct research on this racemic drug online and using the CSU library and write a 500 word summary on the drugs pharmacology, toxicology, pharmacokinetics, and metabolism.
In the summary, indicate how chirality and stereoisomers could influence the pharmacology, bioactivity, toxicology, pharmacokinetics, and metabolism.
Build a molecular model of both enantiomers of this drug and take a photo of the enantiomers oriented in a way that it clearly shows the non superimposability of the mirror images.
Point out the chiral center or centers and indicate absolute configuration (R or S) of each chiral center.
References:
Landoni MF, Soraci A. (2001) Pharmacology of chiral compounds: 2-Arylpropionic acid derivatives. Current Drug Metabolism. 2(1):37–51.
Marzo A, Heftman E. (2002) Enantioselective analytical methods in pharmacokinetics with specific reference to genetic polymorphic metabolism. Journal of Biochemical and Biophysical Methods. 54(1-3):57–70.
Nguyen, L. A., He, H., & Pham-Huy, C. (2006). Chiral drugs: an overview. International journal of biomedical science : IJBS, 2(2), 85–100.
