Per-Ola Norrby December 2014 Molecular Modeling in Pharmaceutical Development.
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Transcript of Per-Ola Norrby December 2014 Molecular Modeling in Pharmaceutical Development.
Per-Ola NorrbyDecember 2014
Molecular Modeling in Pharmaceutical Development
Per-Ola NorrbyDecember 2014
Pharma Modeling
Discovery phase
Screening candidate molecules• thousands-millions• pharmacokinetic properties• binding to target
QSARDocking…
Product Development phase
Single moleculesProcessability• Crystal propertiesDegradation• Chemical reactivitySynthesis• Reagent selection• Reaction conditions
Per-Ola NorrbyDecember 2014
Chemical synthesis
PotencySolubility
Permeability
MetabolismPatentability
Stability
Distribution
Toxicology
Processability
Per-Ola NorrbyDecember 2014
Discovery Modeling
Fast methods, many molecules
QSAR, > 106
Docking, molecular mechanics, > 103
MD, 1-100
Fast
Medium
Slow
Candidates
Enriched set
Per-Ola NorrbyDecember 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 NorrbyDecember 2014
Quantum Chemical Reactivity
Calculate all possible species on the path
Calculate the transition states connecting them
BrHN
O
Pd(PtBu3)2
tBuOKN O+
Example: Buchwald-Hartwig reaction
Per-Ola NorrbyDecember 2014
Quantum Chemical Reactivity
Pd BrtBu3P
Pd NtBu3P O
Pd BrtBu3PN
O
H
PdtBu3PN
O
HOtBu
PdtBu3PN
O
H
Pd OtButBu3PN
O
H
Pd OtButBu3P
+200 kJ/mol
G
NPdtBu3P
‡
O
Sunesson, Limé, Nilsson Lill, Meadows, Norrby, JOC 2014, ASAP
Per-Ola NorrbyDecember 2014
Quantum Chemical Reactivity
Simplified!
Pd OtButBu3P
N
O
H
NPdtBu3P
‡
O
�G‡ =
79
kJ/m
ol
Clot, Norrby, inInnovative Catalysis in Organic Synthesis: Oxidation, Hydrogenation, and C-X Bond Forming Reactions, Wiley, 2012
Per-Ola NorrbyDecember 2014
DBU as base in nonpolar solvent
Formation of DBU-H+ Br-
Very costly in non-polar solvent
Per-Ola NorrbyDecember 2014
Bases in polar solvent (DMF)
t-BuO– DBU
Per-Ola NorrbyDecember 2014
Modeling reaction selectivity
G‡
Only TS needed
Per-Ola NorrbyDecember 2014
The High-Energy Intermediate
Selectivity
Approximate selectivity
OAcR
NuR
PdLL
R
Oslob, Åkermark, Helquist, Norrby, Organometallics 1997, 3015
Per-Ola NorrbyDecember 2014
The High-Energy Intermediate
Approximate selectivity
Liljenberg, Brinck, Herschend, Rein, Rockwell, Svensson, J. Org. Chem. 2010, 4696
R
R
Br
R
Br
H
Per-Ola NorrbyDecember 2014
The High-Energy Intermediate
Autoxidation
R H
R
R OO
Per-Ola NorrbyDecember 2014
The Autoxidation tool
R H
RR OO
R OOH
O2
Autoxidation propagation
Bond dissociation energy < 370 kJ/mol R H R H+H
2D-structure 3D-structure
Remove H B3LYP opt
UB3LYP opt
BDE calc.
Andersson, Broo, Evertsson,J. Pharm. Sci. 2014, 103, 1949
Per-Ola NorrbyDecember 2014
Modeling reaction selectivity
G‡
Boltzmann summation1-10 paths
>10 000 possible!
Per-Ola NorrbyDecember 2014
Experimental Optimization
Objectives
ReactivityStabilitySelectivity
Factors
TemperatureH2 PressureSolventBase?Additives?Ligand(s)
Design Points
2-32-3
3-100-50-5
8-500
96 >1 000 000
Optimization space discontinuous – Per Ryberg, SYNFLOW meeting 2011– Dense testing needed
Per-Ola NorrbyDecember 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 NorrbyDecember 2014
Reaction specific force fields
Quantum Mechanics (QM) Molecular Mechanics (MM)
Q2MM
Norrby, Brandt, Rein, J. Org. Chem. 1999, 5845
Per-Ola NorrbyDecember 2014
Asymmetric Dihydroxylation
N
MeO
N
OR
OH
OHcat. OsO4
NMO or K3Fe(CN)6
MUE: 2.5 kJ/mol
Norrby, Rasmussen, Haller, Strassner, HoukJ. Am. Chem. Soc., 1999, 10186.
Fristrup, Jensen, Andersen, Tanner, NorrbyJ. Organomet. Chem. 2006, 2182.
1 10 100 1000 100000.3
3.0
30.0
300.0
3000.0
30000.0
Exp. e.r.
Ca
lc. e
.r.
Per-Ola NorrbyDecember 2014
0000
0000
0000
00000
0000
8
X
0000
0000
0000
00000
0000
8
1
Parameterization from QM data, structures, charges, relative energies.Vibrational data (Hessians) is modified before being used as reference data:
Diagonalization:
Eigenvalue replacement:
Forming the new Hessian:
Q2MM Norrby, J. Mol. Struct. (Theochem) 2000, 506, 9
Per-Ola NorrbyDecember 2014
The Q2MM ProcedureQuantum mechanical
transition states
Structural data(e.g., bond lengts)
Vibrational data(force constants)
Modification of reaction coordinate (minimum)
Set ofQM data
Select force field(MM3*, Amber)
Define new atom& bond types
Guess initialparameters
Generate trial force fields
Sets ofMM data
Comparesets
Bestforce field
Lowest error
Finalforce field
Optimum?
Test againstexperiments
Per-Ola NorrbyDecember 2014
Q2MM
QM TSca 20 atoms
MM TSFF
>100 atoms
Conf. Search∆∆E‡Boltzmann
Eyring, e–∆∆G‡/RT
Exp. ratio
Per-Ola NorrbyDecember 2014
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 NorrbyDecember 2014
Asymmetric Dihydroxylation
N
MeO
N
OR
OH
OHcat. OsO4
NMO or K3Fe(CN)6
MUE: 2.5 kJ/mol
Norrby, Rasmussen, Haller, Strassner, HoukJ. Am. Chem. Soc., 1999, 10186.
Fristrup, Jensen, Andersen, Tanner, NorrbyJ. Organomet. Chem. 2006, 2182.
1 10 100 1000 100000.3
3.0
30.0
300.0
3000.0
30000.0
Exp. e.r.
Ca
lc. e
.r.
Per-Ola NorrbyDecember 2014
Asymmetric Hydrogenation
Donoghue, Helquist, Norrby, Wiest, J. Am. Chem. Soc. 2009, 410
0.001 0.01 0.1 1 10 100 1000 100000.01
0.1
1
10
100
Exp. e.r.
Ca
lc. e
.r.
MUE: 3.2 kJ/mol
Per-Ola NorrbyDecember 2014
Ru-catalyzed ketone reduction
MUE: 2.7 kJ/mol
0.001 0.01 0.1 1 10 1000.001
0.01
0.1
1
10
100
1000
Exp. e.r.
Ca
lc. e
.r.
Limé, Lundholm, Forbes, Wiest, Helquist, Norrby, J. Chem. Theory Comput. 2014, 2427
Per-Ola NorrbyDecember 2014
Natural Q2MM
New:Eigenvector-projected Hessian
DifferentiateEigenvalue fit from Eigenvector fit
Fit w/o lowest mode
Limé, Norrby,
J. Comput. Chem. 2014, in press
Per-Ola NorrbyDecember 2014
Q2MM at AZ
What will the user do?
Existing reaction: New reaction: – Draw substrate – Convince us to develop it – Select reaction – Wait (months) – Push GO – Go to “Existing reaction”
Where are we now?• Manual screening of ligands, few reactions
• Experimental testing under way (Macclesfield)• Tools for implementing new reactions
Under development (with Notre Dame University)• Improved, faster tools for new reactions• Automated Virtual Screening (Target: March 2015)
Elaine Limé
Per-Ola NorrbyDecember 2014
AcknowledgmentDenmarkTorben RasmussenPeter FristrupMårten AhlquistSigne T. Henriksen
Notre DamePaul HelquistOlaf WiestPatrick DonoghueElsa KiekenAaron ForbesEric Hansen
$$$The University of Gothenburg, The Swedish Research Council,AstraZeneca, FP7/SYNFLOW, COST, C3SE/Gothenburg
AstraZenecaTobias ReinPer RybergHans-Jürgen FederselRobert WoodwardRebecca MeadowsSten Nilsson LillSimone TomasiElaine LiméAnders BrooRachel MundayDavid Buttar
U. GothenburgAnna HedströmPer-Fredrik LarssonJonatan KleimarkCharlotte JohanssonPetra RönnholmCarina BäcktorpYlva Sunesson
LundUlf RydePatrik Rydberg