Simulation Based Approach for Determining Membrane Permeability of Anticancer Drugs

Neetu Singh Yadav and D. Sundar*

Department of Biochemical Engineering and Biotechnology Indian Institute of Technology Delhi, India.

Poor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in the clinical trials. Therefore, prediction of the rate of non-fasciliated permeation of drugs across the bilayer is crucial for drug design, signaling and toxicology. These rates can be estimated using molecular dynamics simulations, in conjunction with inhomogeneous solubility-diffusion model that requires calculation of the potential of mean force (PMF) and diffusitivity of the drug candidates along the lipid bilayer axis. In this study, we have assessed the difference of peremeability of two natural compounds called withanolides, namely, Withaferin A (Wi-A) and Withanone (WN), that have similar structures but differ remarkably in cytotoxicity across a model POPC membrane. An ~0.9μs long umbrella sampling was employed for the calculation of transmembrane PMF for each molecule. The results showed that Wi-A, but not Wi-N, could proficiently transverse through the model membrane. The possible explanation, as showed by grid inhomogeneous solvation theory (GIST), indicates that such difference could be attributed to the difference in the solvation of hydroxyl groups attached to the steroidal ring. This makes passage of Wi-A easier when comapred to WN.