Importance of hydrophobic parameters in identifying appropriate pose of CYP substrates in cytochromes

• The importance of hydrophobic binding forces in cytochromes was described.
• The selective/non-selective regions of active sites in cytochromes were explored.
• Origin of isoform specificity of CYP substrates in cytochromes was delineated.
• A protocol was developed to identify the metabolic profile in cytochromes.

Cytochromes are catalytic enzymes which perform oxidative metabolic reactions on drugs. To determine the primary binding forces of CYP-substrate complex, molecular docking studies were carried out. Molecular docking analysis of several drugs with the enzymes CYP2C9, CYP2D6 and CYP3A4 revealed that hydrophobic interactions play a major role in determining the pose selection between substrates and enzymes. GOLD software with hydrophobic and hydrogen bond constraint was employed to identify the specific interactions which play deterministic role in the pose selection.

The active site of cytochromes contains three regions: base, wall and dome. The wall region is hydrophobic; thus, molecular docking imposing hydrophobic constraint leads to success in SOM prediction.Figure optionsDownload as PowerPoint slide