1. Per-Ola Norrby December 2014 Molecular Modeling in Pharmaceutical Development

2. Per-Ola Norrby December 2014 Pharma Modeling Discovery phase Screening candidate molecules thousands-millions pharmacokinetic properties binding to target QSAR Docking … Product Development phase Single molecules Processability Crystal properties Degradation Chemical reactivity Synthesis Reagent selection Reaction conditions

3. Per-Ola Norrby December 2014 Chemical synthesis Potency Solubility Permeability Metabolism Patentability Stability Distribution Toxicology Processability

4. Per-Ola Norrby December 2014 Discovery Modeling Fast methods, many molecules QSAR, > 10 6 Docking, molecular mechanics, > 10 3 MD, 1-100 Fast Medium Slow Candidates Enriched set

5. 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

6. Per-Ola Norrby December 2014 Quantum Chemical Reactivity Calculate all possible species on the path Calculate the transition states connecting them Example: Buchwald-Hartwig reaction

7. Per-Ola Norrby December 2014 Quantum Chemical Reactivity Sunesson, Limé, Nilsson Lill, Meadows, Norrby, JOC 2014, ASAP

8. 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

9. Per-Ola Norrby December 2014 DBU as base in nonpolar solvent Formation of DBU-H + Br - Very costly in non-polar solvent

10. Per-Ola Norrby December 2014 Bases in polar solvent (DMF) t-BuO – DBU

11. Per-Ola Norrby December 2014 Modeling reaction selectivity  G ‡ Only TS needed

12. Per-Ola Norrby December 2014 The High-Energy Intermediate SelectivityApproximate selectivity Oslob, Åkermark, Helquist, Norrby, Organometallics 1997, 3015

13. Per-Ola Norrby December 2014 The High-Energy Intermediate Approximate selectivity Liljenberg, Brinck, Herschend, Rein, Rockwell, Svensson, J. Org. Chem. 2010, 4696

14. Per-Ola Norrby December 2014 The High-Energy Intermediate Autoxidation

15. Per-Ola Norrby December 2014 The Autoxidation tool Autoxidation propagation Bond dissociation energy < 370 kJ/mol 2D-structure3D-structure Remove H B3LYP opt UB3LYP opt BDE calc. Andersson, Broo, Evertsson, J. Pharm. Sci. 2014, 103, 1949

16. Per-Ola Norrby December 2014 Modeling reaction selectivity  G ‡ Boltzmann summation 1-10 paths >10 000 possible!

17. Per-Ola Norrby December 2014 Experimental Optimization Objectives Reactivity Stability Selectivity Factors Temperature H 2 Pressure Solvent Base? Additives? Ligand(s) Design Points 2-3 3-10 0-5 8-500 96  >1 000 000 Optimization space discontinuous – Per Ryberg, SYNFLOW meeting 2011 – Dense testing needed

18. 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

19. Per-Ola Norrby December 2014 Reaction specific force fields Quantum Mechanics (QM)Molecular Mechanics (MM) Q2MM Norrby, Brandt, Rein, J. Org. Chem. 1999, 5845

20. Per-Ola Norrby December 2014 Asymmetric Dihydroxylation MUE: 2.5 kJ/mol Norrby, Rasmussen, Haller, Strassner, Houk J. Am. Chem. Soc., 1999, 10186. Fristrup, Jensen, Andersen, Tanner, Norrby J. Organomet. Chem. 2006, 2182.

21. Per-Ola Norrby December 2014 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

22. Per-Ola Norrby December 2014 The Q2MM Procedure

23. Per-Ola Norrby December 2014 Q2MM QM TS ca 20 atoms MM TSFF >100 atoms Conf. Search∆∆E ‡ Boltzmann Eyring, e –∆∆G ‡ /RT Exp. ratio

24. Per-Ola Norrby December 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)

25. Per-Ola Norrby December 2014 Asymmetric Dihydroxylation MUE: 2.5 kJ/mol Norrby, Rasmussen, Haller, Strassner, Houk J. Am. Chem. Soc., 1999, 10186. Fristrup, Jensen, Andersen, Tanner, Norrby J. Organomet. Chem. 2006, 2182.

26. Per-Ola Norrby December 2014 Asymmetric Hydrogenation Donoghue, Helquist, Norrby, Wiest, J. Am. Chem. Soc. 2009, 410 MUE: 3.2 kJ/mol

27. Per-Ola Norrby December 2014 Ru-catalyzed ketone reduction MUE: 2.7 kJ/mol Limé, Lundholm, Forbes, Wiest, Helquist, Norrby, J. Chem. Theory Comput. 2014, 2427

28. Per-Ola Norrby December 2014 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

29. Per-Ola Norrby December 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

30. Per-Ola Norrby December 2014 Acknowledgment 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 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