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Insights in Enzyme Research
ISSN: 2573-4466
E u r o S c i C o n C o n g r e s s o n
Enzymology and
Molecular Biology
A u g u s t 1 3 - 1 4 , 2 0 1 8
P a r i s , F r a n c e
Enzymology 2018
We previously combined molecular dynamics (classical or simulated
annealing) with ligand-receptor contacts analysis as means to extract
valid pharmacophore model(s) from single ligand-receptor complexes.
However, molecular dynamics methods are computationally expensive
and time consuming. Here we describe a novel method for extracting valid
pharmacophore model(s) from a single crystallographic structure or form
homology modelled structure within reasonable time scale. The new method
is based on ligand-receptor contacts analysis following energy relaxation
of predetermined set of randomly deformed complexes generated from the
targeted crystallographic structure. Ligand-receptor contacts maintained
across many deformed/relaxed structures are assumed to be critical and used
to guide pharmacophore development. This methodology was implemented
to develop valid pharmacophore models for different enzymes (i.e., PI3K-γ,
and Akt3). The resulting pharmacophore models were validated by receiver
operating characteristic (ROC) analysis against inhibitors extracted from
CHEMBL database. Additionally, we implemented pharmacophores extracted
from PI3K-γ to search for new inhibitors from the national cancer institute list
of compounds. The process culminated in new PI3K-γ/mTOR inhibitory leads
of low micromolar IC50s.
Biography
Dr. Ma'mon Hatmal has a PhD in Philosophy of Biochemistry
and Molecular Biology with Honors from the University of
Southern California (USC), USA (2012). He is now an assistant
professor and a researcher at the Hashemite University/
Jordan. He was a Fulbright post-doctoral researcher at USC,
USA (2017). He received many awards for his performance
and research (i.e., Philadelphia University International award
for best scientific software). His current research interests
focus mainly on bioinformatics, in particular computer-aided
molecular design and discovery towards new bioactive
compounds, and computational prediction of 3D structures
of biological macromolecules. He published couple of novel
approaches of combining molecular dynamics (classical,
simulated annealing, and stochastic deformation/relaxation)
with contact analysis to extract valid pharmacophore model(s)
from a single crystallographic structure within a reasonable
time scale, these approaches culminated in new inhibitory leads
(against enzymes involved in cancer and other diseases) of low
micromolar and sub-micromolar IC50s.
Combining stochastic deformation/relaxation and intermolecular
contacts analysis as a novel approach for pharmacophore modeling
based on X-Ray or homology-modelled ligand-receptor complexes
Mamon Hatmal
The Hashemite University, Jordan
Mamon Hatmal, Insights Enzyme Res 2018, Volume 2
DOI: 10.21767/2573-4466-C1-002