Title:Molecular Dynamics Simulations of HDAC-ligand Complexes Towards
the Design of New Anticancer Compounds
Volume: 23
Issue: 29
Author(s): Varun Dewaker and Yenamandra S. Prabhakar*
Affiliation:
- Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow,
226031, India
Keywords:
QSAR, HDAC, Drug design, Molecular dynamics simulation, Non-bonding energy, Protein-ligand complex.
Abstract: Quantitative Structure-activity Relationship (QSAR) studies gained a foothold in the
mid-1960s to rationalise the biological activity of medicinally important compounds. Since then,
the advancements in computer hardware and software added many new techniques and areas to
this field of study. Molecular dynamics (MD) simulations are one such technique in direct drug design
approaches. MD simulations have a special place in drug design studies because they decode
the dynamics of intermolecular interactions between a biological target and its potential ligands/inhibitors.
The trajectories from MD simulations provide different non-bonding interaction parameters
to assess the compatibility of the protein-ligand complex and thereby facilitate the design of
prospective compounds prior to their wet-lab exploration. Histone deacetylases (HDACs) play a
key role in epigenetics and they are promising drug targets for cancer and various other diseases.
This review attempts to shed some light on the modelling studies of HDAC inhibitors as anticancer
agents. In view of the advantages of MD simulations in direct drug design, this review also
discusses the fragment-based approach in designing new inhibitors of HDAC8 and HDAC2, starting
from the interaction energies of ligand fragments obtained from the MD simulations of respective
protein-ligand complexes. Here, the design of new anticancer compounds from largazole thiol,
trichostatin A, vorinostat, and several other prototype compounds are reviewed. These studies
may stimulate the interest of medicinal chemists in MD simulations as a direct drug design approach
for new drug development.
