Transcript PowerPoint-presentation

Molecular Modeling in
Pharmaceutical Development
Per-Ola Norrby
December 2014
Pharma Modeling
Discovery phase
Product Development phase
Screening candidate molecules
• thousands-millions
• pharmacokinetic properties
• binding to target
Single molecules
Processability
• Crystal properties
Degradation
• Chemical reactivity
Synthesis
• Reagent selection
• Reaction conditions
QSAR
Docking
…
Per-Ola Norrby
December 2014
Potency
Chemical
synthesis
Permeability
Distribution
Metabolism
Patentability
Toxicology
Per-Ola Norrby
December 2014
Solubility
Stability
Processability
Discovery Modeling
Candidates
Fast methods, many molecules
Fast
QSAR, > 106
Docking, molecular mechanics, > 103
Medium
MD, 1-100
Slow
Enriched set
Per-Ola Norrby
December 2014
Product Development Modeling
Accurate methods, single molecules, devices
Synthesis route, degradation possibilities
 Databases of reactions, ICSynth, Zeneth
Synthesis or degradation predictions
 QM, DFT, MM
Material properties
 Crystal packing, periodic boundaries, MM, DFT
Distribution, shelf life
 Kinetics networks, simulation
Flow dynamics
 Finite elements
Per-Ola Norrby
December 2014
Quantum Chemical Reactivity
Example: Buchwald-Hartwig reaction
Calculate all possible species on the path
Calculate the transition states connecting them
Per-Ola Norrby
December 2014
Quantum Chemical Reactivity
Sunesson, Limé, Nilsson Lill,
Meadows, Norrby, JOC 2014, ASAP
Per-Ola Norrby
December 2014
Quantum Chemical Reactivity
Simplified!
Clot, Norrby, in
Innovative Catalysis in Organic
Synthesis: Oxidation, Hydrogenation,
and C-X Bond Forming Reactions,
Wiley, 2012
Per-Ola Norrby
December 2014
DBU as base in nonpolar solvent
Formation of DBU-H+ BrVery costly in non-polar solvent
Per-Ola Norrby
December 2014
Bases in polar solvent (DMF)
t-BuO–
DBU
Per-Ola Norrby
December 2014
Modeling reaction selectivity
G‡
Only TS
needed
Per-Ola Norrby
December 2014
The High-Energy Intermediate
Selectivity
Approximate selectivity
Oslob, Åkermark, Helquist, Norrby,
Organometallics 1997, 3015
Per-Ola Norrby
December 2014
The High-Energy Intermediate
Approximate selectivity
Liljenberg, Brinck, Herschend, Rein, Rockwell, Svensson,
J. Org. Chem. 2010, 4696
Per-Ola Norrby
December 2014
The High-Energy Intermediate
Autoxidation
Per-Ola Norrby
December 2014
The Autoxidation tool
Bond dissociation energy < 370 kJ/mol
2D-structure
3D-structure
Remove H
B3LYP opt
UB3LYP opt
Autoxidation propagation
BDE calc.
Andersson, Broo, Evertsson,
J. Pharm. Sci. 2014, 103, 1949
Per-Ola Norrby
December 2014
Modeling reaction selectivity
G‡
Boltzmann
summation
1-10 paths
>10 000 possible!
Per-Ola Norrby
December 2014
Experimental Optimization
Objectives
Factors
Reactivity
Stability
Selectivity
Temperature
H2 Pressure
Solvent
Base?
Additives?
Ligand(s)
Design Points
2-3
2-3
3-10
0-5
0-5
8-500
96  >1 000 000
Optimization space discontinuous – Per Ryberg, SYNFLOW meeting 2011
– Dense testing needed
Per-Ola Norrby
December 2014
Modeling Methods
Needed: transition states (TS) for all pathways
Quantum Mechanics, DFT
+ Accurate
− Time consuming, hours-days for each TS
− TS search not automated
Molecular Mechanics
+ Fast, seconds or less per structure
+ Adjustable parameters
+ Automated conformer search
? Accurate ? (target: 2 kJ/mol)
− Not available for metals, TS
Per-Ola Norrby
December 2014
Reaction specific force fields
Q2MM
reactant
energy
energy
TS
TSFF
product
reaction progress
Quantum Mechanics (QM)
Molecular Mechanics (MM)
Norrby, Brandt, Rein, J. Org. Chem. 1999, 5845
Per-Ola Norrby
December 2014
Asymmetric Dihydroxylation
N
R O
10000.0
MeO
OH
1000.0
N
cat. OsO4
NMO or K3Fe(CN) 6
Calc. e.r.
100.0
OH
10.0
MUE: 2.5 kJ/mol
1.0
Norrby, Rasmussen, Haller, Strassner, Houk
J. Am. Chem. Soc., 1999, 10186.
0.1
1
10
100
1000
Exp. e.r.
10000
Per-Ola Norrby
December 2014
Fristrup, Jensen, Andersen, Tanner, Norrby
J. Organomet. Chem. 2006, 2182.
Q2MM
Norrby, J. Mol. Struct. (Theochem) 2000, 506, 9
Parameterization from QM data, structures, charges, relative energies.
Vibrational data (Hessians) is modified before being used as reference data:
Diagonalization:
H¢
H = XT WX
H
Eigenvalue replacement:
- l1 Þ l x , W Þ W¢
Forming the new Hessian:
H¢ = XT W¢X
  1

 0
 0

 0
 0

0

0 0 0 0
0  0 0

0 0 8 0 
0 0 0 
0
0
0
Per-Ola Norrby
December 2014
 X

 0
 0

 0
 0

0

0 0 0 0
0  0 0

0 0 8 0 
0 0 0 
0
0
0
The Q2MM Procedure
Per-Ola Norrby
December 2014
Q2MM
QM TS
ca 20 atoms
MM TSFF
>100 atoms
∆∆E‡
Boltzmann
‡
Eyring, e–∆∆G /RT
Exp. ratio
Per-Ola Norrby
December 2014
Conf. Search
Q2MM for AD: Development
B3LYP for small models (ca 50, different R).
Haller, Strassner, Houk, J. Am. Chem. Soc. 1997, 119, 8031.
Define Q2MM force field for the region around the reaction center.
Fit structures, energies, vibrations, charges to the B3LYP results for all small
models.
Use Q2MM model for
real system
(ca 1/day/cpu)
Per-Ola Norrby
December 2014
Asymmetric Dihydroxylation
N
R O
10000.0
MeO
OH
1000.0
N
cat. OsO4
NMO or K3Fe(CN) 6
Calc. e.r.
100.0
OH
10.0
MUE: 2.5 kJ/mol
1.0
Norrby, Rasmussen, Haller, Strassner, Houk
J. Am. Chem. Soc., 1999, 10186.
0.1
1
10
100
1000
Exp. e.r.
10000
Per-Ola Norrby
December 2014
Fristrup, Jensen, Andersen, Tanner, Norrby
J. Organomet. Chem. 2006, 2182.
Asymmetric Hydrogenation
100
Calc. e.r.
10
1
0.1
0.01
0.001
0.1
10
Exp. e.r.
MUE: 3.2 kJ/mol
Per-Ola Norrby
December 2014
1000
Donoghue, Helquist, Norrby, Wiest,
J. Am. Chem. Soc. 2009, 410
Ru-catalyzed ketone reduction
O
1000
Ar2
P
H
H2
N
Ru
P
Ar2
H
N
R2
*
*
H2
Calc. e.r.
100
10
1
0.1
0.01
OH
*
Limé, Lundholm, Forbes, Wiest, Helquist, Norrby,
J. Chem. Theory Comput. 2014, 2427
Per-Ola Norrby
December 2014
0.001
0.001 0.01
0.1
1
Exp. e.r.
10
MUE: 2.7 kJ/mol
100
Natural Q2MM
New:
Eigenvector-projected
Hessian
Differentiate
Eigenvalue fit from
Eigenvector fit
Fit w/o lowest mode
Limé, Norrby,
J. Comput. Chem. 2014, in press
Per-Ola Norrby
December 2014
Q2MM at AZ
Where are we now?
• Manual screening of ligands, few reactions
• Experimental testing under way (Macclesfield)
• Tools for implementing new reactions
Elaine Limé
Under development (with Notre Dame University)
• Improved, faster tools for new reactions
• Automated Virtual Screening (Target: March 2015)
What will the user do?
Existing reaction:
– Draw substrate
– Select reaction
– Push GO
Per-Ola Norrby
December 2014
New reaction:
– Convince us to develop it
– Wait (months)
– Go to “Existing reaction”
Acknowledgment
AstraZeneca
Tobias Rein
Per Ryberg
Hans-Jürgen Federsel
Robert Woodward
Rebecca Meadows
Sten Nilsson Lill
Simone Tomasi
Elaine Limé
Anders Broo
Rachel Munday
David Buttar
U. Gothenburg
Anna Hedström
Per-Fredrik Larsson
Jonatan Kleimark
Charlotte Johansson
Petra Rönnholm
Carina Bäcktorp
Ylva Sunesson
Lund
Ulf Ryde
Patrik Rydberg
Denmark
Torben Rasmussen
Peter Fristrup
Mårten Ahlquist
Signe T. Henriksen
Notre Dame
Paul Helquist
Olaf Wiest
Patrick Donoghue
Elsa Kieken
Aaron Forbes
Eric Hansen
$$$
The University of Gothenburg, The Swedish Research Council,
AstraZeneca, FP7/SYNFLOW, COST, C3SE/Gothenburg
Per-Ola Norrby
December 2014