1. High Throughput Experimentation: Computational Requirements John M. Newsam Molecular Simulations Inc. (A Pharmacopeia subsidiary) “Workshop on Combinatorial Methods for Materials Discovery” ATP Fall National Meeting Atlanta, GA Wednesday November 18th 1998

2. Potential Hindrances? Patent profusion –vigilance Unmet expectations –set reasonably Infrastructure cost –hindrance for academics Lack of standards –premature for hardware Inertia –resistance to change, short-term delivery focus

3. High-throughput Experimentation Lead compounds for resynthesis and secondary testing Testing requirements drive synthesis format Library Design QSAR # # Quantitative Structure-Activity relationships Pooled, parallel or discrete Synthesis Primary Testing Performance in specific application Physical, mechanical etc. processing Processing Characterization of composition, purity, phases, structure Analytical

4. Infrastructure Needs Vertical and horizontal integration Adaptable Modular Geared for huge throughput Broadly deployable

5. New 1536 well HTS Format 1536 wells, 2  l well volume Corning Science Products joint design Automated 96  1536 reformatter  l-level fluids dispensing Oxidative and evaporative loss reduced Engineering Solution

6. Process and Data Management Data Base Engines Oracle Materials Algorithms Display Statistics User Input & Workstation Interfaces Chemistry & Materials Input Workstation & Oracle Forms Materials Specific Tables Analysis, Display and Data Access Server-based Processing Molecular Simulation

7. Luminescence data for a library of mixed metal oxides under 254nm UV irradiation Data from E.Danielson et al., Science 279 (1998) 831

8. Some Specific Technology Needs Hits vs misses; improvement criteria Descriptors Experiment decision support Abstracted feature models (AFMs) Process optimization Simulation for scale-up Sensor data (unravelling response of arrays)

9. Which experiments should be done ? Making it practical: computation –100 R1, 100 R2, 100 R3, 100 R4  10 8 – 50,000 compounds/week  40 years How do we manage the process ? What knowledge do the experiments yield ? Computation Solution ‘Hard materials’ M2M2 M1M1 X + Temp Scaffold ‘Soft materials’ R1R1 R2R2 R3R3 R4R4

10. Computation Solution Compound library design Library Specification –Molecular: Product or Reaction-based –Polymers, Heterogeneous catalysts ? Library Design –Diversity and similarity metrics –Similarity Selection –Array and mixture design Library Comparison Library Focussing –Active site model (atomic or abstracted) –QSAR Model C 2.Diversity C 2.LibCompare C 2.LibSelect World Drug Index of 35,873 compounds in a space of principal components

11. Abstracted Feature Models R.C.Willson Abstraction of key features Based on activity data Interesting ‘active’ definition

12. Descriptors Topological Fragments Receptor surface Structural Information-content Spatial Electronic Thermodynamic Conformational Quantum mechanical Descriptor Families C 2.Descriptor+ C 2.MFA C 2.QSAR+ C 2.Synthia Products Plus Molecular and Quantum Methods Descriptors - calculable molecular attributes that govern particular macroscopic properties Computation Solution

13. Available, occupiable volume & framework density descriptors (104 zeolite and zeolite-related framework types) Correlative methods in catalyst design: Expert systems, neural networks and structure-activity relationships, in “Advances in Catalyst Design” Catalyst Advance Program (CAP) Report, The Catalyst Group, PA; in press (1998)

14. Structure-Activity Relationships C 2.QSAR+ C 2.GA Products Linear regression Stepwise & multiple linear regression Principal components analysis Partial least squares Genetic algorithm Genetic function approximation Statistical Models DescriptorsCorrelative Methods Properties E.g. K.F. Moschner and A. Cece, “Development of a General QSAR for Predicting Octanol-Water Partition Coefficients and its Application to Surfactants,” ASTM STP 1218 (1995); MSI C 2 QSAR manual April 1997. Computation Solution

15. Oil Field Corrosion Inhibitors Organics H. Gråfen et al., Werkstoff und Korrosion, Vol. 36, 407 (1985) Benzimidazolines function at cathodic sites Library studied by Kuron et al. (1985) Key descriptors Terminal N charge 3-substituted N charge Octanol-water logP Moment of inertia M.Doyle

16. Conclusion Computational infrastructure needs Specific technology needs Role of computation –process management system –experiment decision support –data visualization and analysis –knowledge from the experimental data Integration