Recognizing the fact that many novel drugs failed to pass clinical evaluation is
mainly due to their poor ADME/T properties, the recent focus of our lab
has been developing an integrated computational methodology that can help predict the ADME/T
properties of new candidate compounds in the early phases of drug development. The first part of
this integrated methodology includes identification of substrates or
inhibitors of metabolic enzymes, e.g., cytochrome P450 and the efflux
pump, e.g., P-glycoprotein, which will facilitate homology modeling,
docking, and molecular dynamics simulations, and binding free energy
calculations. The second part will include QSAR prediction of intestinal
permeability, blood brain barrier, among other important ADME/T
properties based on passive transport mechanism.
In the past, we have proposed the "relaxed complex" scheme that can
accommodate receptor flexibility for structure-based drug design, and it
has been demonstrated that this computational approach can reach the
same accuracy as the "SAR by NMR" method for lead optimization.
Along the same line we will continue to explore the significance of
protein flexibility for molecular recognition.
Besides the development of new computational
methodology, we have also been developing new antitumor agents based on
virtual screening of large chemical databases. The current approach is
to design a potent inhibitor to block the function of
farnesyltransferase, which plays a very important role for the
post-translational modification of the Ras protein.
Continued with our previous work, we are also
investigating the interactions of toxic peptides with biological
membranes. We have applied the Atomic Force Microscopy simulations to
unravel the interaction of a single peptide and a peptide channel with a
lipid bilayer. This could provide us with invaluable dynamical insights
from such non-equilibrium processes. We are also investigating the
molecular mechanism of selected targeting to cancer cells of some toxic
In addition, we are also investigating the
activation and gating mechanisms of ion channels, as well as the
selection permeation of ion channels. The methodologies employed are
molecular dynamics and Brownian dynamics simulations. We could also
evaluate the association rate constants of membrane proteins to a
vesicle under various conditions based on massive Brownian simulation.
We welcome people with different background, e.g.,
physics, chemistry, mathematics, computer sciences, pharmacy, and so on,
to join our lab for these multidisciplinary researches.