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Receptor-based design techniques use information
about the structure of a drug target (receptor) as
a basis for the design of lead compounds. This
includes applications to address critical
receptor-based design tasks, such as ligand
docking, virtual screening, lead optimization.
From humble beginnings by great Austrian and
British scientists such as Perutz and Kendrew,
protein structure determination has become a major
scientific and commercial enterprise. With the
genome as a road map protein structures are solved
faster and more routinely than ever before. The
primary purpose of having the three dimensional
coordinates of a protein, or protein complex, is to
elucidate mode of action. How do proteins do what
they do, and how can we affect what it is they do?
It has been a common, and often incorrect, tenet
that given the structure function will be obvious.
And indeed broad but useful characterizations can
often be made: a DNA binding protein will have a
decidedly positive electrostatic area around the
binding side, an enzyme will typically have a deep,
water inaccessible pocket. However, the detailed
description of mechanism is rarely revealed,
largely because of weakness in our understanding of
the physics of solvation and electrostatics.
Proteins are very complex systems, even when they
look simple.
OpenEye is contributing both scientifically and
with software to this burgeoning field, from
crystallography to physical property calculation to
ligand docking. Our approach is to apply the same
technologies to proteins that have been so
successfully applied to the small molecule world.
Shape and electrostatics are even more important to
the understanding of proteins than they are the
behavior of the ligands that bind to them.
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FRED-
extremely fast, systematic docking search
for ligand binding within a protein active
site
A docking program that fits molecules
into the active site of a protein based
primarily on shape complementarity.
Gaussian shape functions are used to
define the interaction of protein and
ligand, which results in a huge advantage
in performance. So much so that all poses
(rotations and translations) within a
given tolerance can be examined in less
time than stochastic or rule-based methods
(typically, single conformers in
milliseconds). Although FRED can use
ligand information (allowing constraints
to be applied to chemical
functionalities), it works primarily as a
fast screening tool for Large Scale
Virtual Screening.
Seascape Scientific Partner:OpenEye
Scientific Software, New Mexico
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AFITT-
crystallographic refinement and analysis
AFITT, a crystallographic offering,
allows visualization and manipulation of
protein structure and electron density. It
features novel, real-space refinement of
both ligands and side-chains with the MMFF
force-field, easy access to commonly
available packages and facile handling of
ligand chemistry. Available on many
platforms.
Seascape Scientific Partner:OpenEye
Scientific Software, New Mexico
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QUACPAC-
quality charge states and charges for
small molecules and proteins
In addition to providing methods of
applying partial charges to proteins, the
protein_pka module can estimate both
charge states and tautomer preferences
both for apo and ligand complexed
proteins. Based on the ZAP toolkit, OEChem
and MMFF, protein_pka is essential
software for correct protein physics.
Seascape Scientific Partner:OpenEye
Scientific Software, New Mexico
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VIDA II -
molecular visualization and data analysis
on very large datasets
Protein visualization is an important
aspect of structural biology. VIDA II
offers PB electrostatics, secondary
structure depiction, surface rendering and
selection, proximity analysis, electron
density visualization, split view and
multi-paned views, stereo and high-quality
image construction all in a simple,
multi-platform package.
Seascape Scientific Partner:OpenEye
Scientific Software, New Mexico
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