ABSTRACT
Abstract ................................................................................................. 249 6.1 Introduction .................................................................................. 249
6.1.1 S-Oxidation ...................................................................... 249 6.1.2 Metabolism in TZD and Toxicity ..................................... 251
6.2 Methodology ................................................................................ 257 6.2.1 Molecular Docking .......................................................... 257 6.2.2 Comparison with Other Docking Software: Genetic
Optimization for Ligand Docking (GOLD) and FlexX ... 258 6.2.3 General Parameters Chosen for Docking Using Glide ... 259 6.2.4 Ligands ............................................................................. 260 6.2.5 Proteins ............................................................................ 260
6.3 Discussion And Results................................................................ 261 6.3.1 Molecular Docking Analysis of Major Sulfide-Unit
Containing Drugs into the Active Site of CYP450 ........... 261
6.3.2 Summary of Molecular Docking Results ......................... 264 6.3.3 Comparison of Scoring Function ..................................... 266
6.4 Conclusion ................................................................................... 268 Keywords .............................................................................................. 269 References ............................................................................................. 269 Abstract ................................................................................................. 275
ABSTRACT
The glitazones are the important class of anti-diabetic drugs, consisting of a thiazolidinedione (TZD) ring in their structure. The metabolic reactions of several important sulfide (-S-) containing drugs, such as glitazones and diclofenac involve S-oxidation as the first and essential step. However, the detailed mechanism of S-oxidation reaction of these drugs by cytochromes P450 (CPY) has not been explored at the molecular level. In this chapter, initially, a review of already reported computational studies, including quantum chemical studies, on S-oxidation is discussed. A database of sulfide and sulfoxide unit containing drugs was prepared. The molecular docking analysis was carried out to predict the probability of S-oxidation in these drugs. A comparative analysis has been carried out to establish a molecular docking protocol which can successfully predict the S-oxidation reaction. The molecular docking analysis was carried out on three major CYP isoforms using Glide software of Schrodinger package. The importance of oxygen atom on heme iron, (Cpd) I [iron (IV)-oxo] to mimic CYP450 in determining S as the site of metabolism (SOM) was critically analyzed. Thus, this chapter reviews the usefulnss of molecular docking and quantum chemical methods in providing significant details regarding SOM and mechanistic details for sulfide and sulfoxide unit containing drugs, which can be utilized as a protocol to predict SOM for any new lead, including anti-diabetic compounds, during the early phase of drug discovery.
