Drug Design with Parallel

footballsyrupSoftware and s/w Development

Dec 1, 2013 (3 years and 8 months ago)

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Drug Design with Parallel
Computing

Developing a Novel Drug

Time:



12 years (average)




10 years to get the patent

Money:


350 million US dollars

Human resources:

150 researchers

Terminology


Molecule


Atoms structure bounded by
electrostatic forces.


Primary structure


The amino acid sequence


Secondary structure


Helices, sheets and turns


Tertiary structure


Side chain packing in the
3D structure

Terminology


cont.


Cell


The smallest living unit. Each cell has a
DNA, which is a chain of Amino acids, and is
unique for that specific creature.



Virus


A molecule with an Active part, and a
DNA. The active part of the virus connects to a
living cell’s membrane, and injects the DNA into
the cell. The virus then uses the cell resources to
breed its own DNA, instead of the cell’s DNA.



Peptide


The active part of a molecule


What is Drug Design

Disease caused by a virus
(protein molecules)

Remedy: Blocking of the
active site of the virus with
peptids

Peptor


Main Idea


Interaction between proteins initiated by
peptides


small loops on the protein edge.


SCAPLs


Small Cyclic Analogs of Protein
Loops.

The molecule manufactured by Peptor
which mimic these peptides, without
actually building the whole protein.

Peptor


Technique Overview


Building Peptide libraries.


Screening libraries for initial
candidates


Molecular dynamics simulation, to get
most adequate candidates.


Experimental screening.


Searching for the right SCAPL.

Building
Peptide
Libraries

Molecular
Dynamics

Experimental
Screening

Searching for
the Right
SCAPL

Screening for
Initial
Candidates

Predicting structures of
peptidomimetics molecules

SCAPL

Peptide



Calculated



Experimental

Building
Peptide
Libraries

Molecular
Dynamics

Experimental
Screening

Searching for
the Right
SCAPL

Screening for
Initial
Candidates

Design of Virtual Libraries

Natural
Peptides

Chemical
Built
Peptides

Virtually
Built
Peptides

Suggestions for Synthesis

Efficient Algorithm for
Library Assembly

Building
Peptide
Libraries

Molecular
Dynamics

Experimental
Screening

Searching for
the Right
SCAPL

Screening for
Initial
Candidates

Molecular Dynamics

Building
Peptide
Libraries

Molecular
Dynamics

Experimental
Screening

Searching for
the Right
SCAPL

Screening for
Initial
Candidates


Testing reaction
between protein
molecules in a
virtual 3D world.


Using heavy duty
parallel software and
hardware, spare up
to 6 years of
experiments, and
millions of dollars.


Example will be
reviewed further on.

Peptor’s Drug Design


Libraries of many different peptides are tagged
with a DNA fraction, and fused into a carrying
cell.


All cells are mixed with the target molecules.


The cells that bounded to the target are screened,
and the chemical composition of the peptides is
easily read out from the DNA tag.


Now we need to find a good carrier

for the peptide.

Building
Peptide
Libraries

Molecular
Dynamics

Experimental
Screening

Searching for
the Right
SCAPL

Screening for
Initial
Candidates

Identifying Active sites in sets of molecules
containing many degrees of freedom


Trying to find SCAPLs that have the same
peptides found in previous stage.


Searching in databases of 10
20

items,

and getting results within few hours.

Building
Peptide
Libraries

Molecular
Dynamics

Experimental
Screening

Searching for
the Right
SCAPL

Screening for
Initial
Candidates

Molecular Dynamics


4 stages needed for parallelizing:


Allocate work among PEs.


Each PE should have (almost) all atom
decomposition.


Each PE should have (almost) all force matrix.


Each PE should have the spatial decomposition.

Molecular Dynamics


The potential field of an atom


Bounded forces


Bonds


Angles


Torsions


Non
-
bounded terms


Simulation steps


(see hand made transparencies)


Source, the serial version


To go parallel, needed collective communication

Molecular Dynamics by

CRAY T3E

Cray T3E

Processor



DEC Alpha

(PE)



21164

Number of Pes


256 + 8




Command Pes

DRAM



128MB/PE x 128 PEs




256MB/PE x 128 PEs

CACHE/PE


Primary 8KB




Secondary 96KB

Disk Space


200GB

Peak Performance


307Gflops

O.S



Unicos/mk 2.0.4

Available Compilers

PG
-
HPF, C, C++,




Fortran F90

Parallel Libraries


MPI, PVM, SHMEM

COST?

Cost/performance?

Molecular Dynamics by

TR2000,

The idea of application oriented
parallel computer


(see hand made transparencies)