Combine ligand and structure based methodologies to probe stereo-selectivity of CYP3A4 inhibitors

Abstract

Cytochrome P450 (CYP-P450) enzymes play critical role in the metabolic processes of the body. These microsomal proteins are involved in the breakdown and detoxification of various xenobiotics, nutrients and clinically administered drugs. The CYP3A family is the largest subfamily of the CYP isoforms in the liver. There are at least four isoforms including 3A4, 3A5, 3A7 and 3A43 of which 3A4 is the most abundant hepatic microsomal enzyme involved in the drug metabolism. Several drugs have tendency to inhibit the normal physiological functioning of CYP3A4 with varying potencies thus, resulting in varying toxic effects. In a quest to avoid CYP3A4 inhibition related drug toxicity, various studies reported the 3D interaction patterns of the CYP3A4 inhibitors and substrates. However, until now no report about molecular level interaction of stereoisomeric drugs with CYP3A4 is available. Since these interactions takes place in asymmetric space, overlooking the stereochemistry of the ligands can compromise the accuracy of various in silico structure based methodologies. Therefore, a detailed knowledge about 3D structural features important for the inhibition of CYP3A4 and stereoselectivity of its inhibitors are noteworthy for analysis. In silico approaches for predicting CYP inhibition potential of stereoisomeric drugs are lucrative as they may be applied to whole set of chemical libraries at the outset of the drug discovery process, usually at very small cost investment at in vivo level. In that way, the in silico models offer considerable potential for reducing the number of experimental studies required for compound selection and for improving the success rate. Therefore, in this project we employed both structure based and ligand based in silico methods to explore the stereo selectivity as well as ligand interaction profiles of CYP3A4 stereo-isomeric inhibitors. Difference between interaction patterns of stereoisomers of CYP3A4 inhibitors was analyzed, which was further reinforced by building GRIND model for analysis of difference in 3D Abstract 1 structural features among isomeric pairs of CYP3A4 inhibitors. Our results demonstrate that the difference in inhibitory potency of different stereoisomeric pairs is because of difference in their interaction pattern within the binding cavity of CYP3A4. 3D structural features that contribute significantly in inhibition are two hydrophobic features at a distance of 12.0 to 12.40Å. The 3D interaction based differentiating features between stereoisomers include two hydrogen bond acceptors at a distance of 16.80 to 17.20Å and one hydrogen bond acceptor and a hydrophobic region at a distance of 18.40 to 18.80Å. Similarly, a hydrogen bond donor and a hydrogen bond acceptor at a distance of about 8.80 to 9.20Å are present in S isomers while absent in R isomeric form of CYP3A4 inhibitors. These results could pave the way towards safer drug development