Computer Aided Molecular Design

Computer Aided Molecular Design : Computer Aided Molecular Design A Strategy for Meeting the Challenges We Face Rico Del Sesto, Liz Corbeil, Carolyn Mordas, Will Polkinghorn

Challenges : Challenges Bacterial Drug Resistance New Diseases (AIDS, HONTA, E. Coli) Agricultural Pest Control Environmentally Benign Synthesis Energy Efficiency (new catalysts)

An Organized Guide : An Organized Guide Build Chemical Insight Discover new molecules Predict their properties

CAMD : CAMD Disciplines Involved Natural Products Chemistry Structure-Function Computer Aided Molecular Design Information Rich Curriculum

Working at the Intersection : Working at the Intersection Structural Biology Biochemistry Medicinal Chemistry Toxicology Pharmacology Biophysical Chemistry Natural Products Chemistry Chemical Ecology Information Technology

Structural Biology : Structural Biology Fastest growing area of biology Protein and nucleic acid structure and function How proteins control living processes

Medicinal Chemistry : Medicinal Chemistry Organic Chemistry Applied to disease Example: design new enzyme inhibitor drugs doxorubicin (anti-cancer)

Pharmacology : Pharmacology Biochemistry of Human Disease Different from Pharmacy: distribution of pharmaceuticals, drug delivery systems

New Ideas From Nature : New Ideas From Nature Natural Products Chemistry Chemical Ecology During the next two decades: the major activity in organismal biology Examples: penicillin, taxol (anti-cancer)

Structure Query : Structure Query

Bell’s Organic Data Base : Bell’s Organic Data Base

Spectroscopic Properties Data Bases : Spectroscopic Properties Data Bases Harold M. Bell , Virginia Polytech. 5,000 compounds ( ISIS, WWW) CRC Properties of Organic Compounds 28,000 (Windows) NIST WebBook Gas Phase IR, MS (WWW) Aldrich, other commercial databases

Working at the Intersection : Working at the Intersection Structural Biology Biochemistry Medicinal Chemistry Toxicology Pharmacology Biophysical Chemistry Natural Products Chemistry Chemical Ecology Information Technology

Principles : Principles Structure-Function Relationships Binding Step 1: Biochemical Mechanism Step 2: Understand and control macromolecular binding

Binding : Binding Binding interactions are how nature controls processes in living cells Enzyme-substrate binding leads to catalysis Protein-nucleic acid binding controls protein synthesis

Principles : Principles Structure-Function Relationships Binding Understand and control binding ->disease Molecular Recognition How do enzymes recognize and bind the proper substrates Guest-Host Chemistry Molecular Recognition in Cyclodextrins

Hosts: b- cyclodextrin : Hosts: b- cyclodextrin

Hexasulfo-calix[6]arenes : Hexasulfo-calix[6]arenes

Molecular Design : Molecular Design Originated in Drug Design Agricultural, Veterinary, Human Health Guest - Host Chemistry Ligands for Inorganic Complexes Materials Science Polymer Chemistry Supramolecular Chemistry Semi-conductors, nonlinear phenomena

CAMD : CAMD Computational techniques to guide chemical intuition Design new hosts or guests Enzyme inhibitors Clinical analytical reagents Catalysts

Information Technology : Information Technology Chemical Abstracts Service registered over one million new compounds last year Expected to increase every year Need to know the properties of all known compounds: pharmaceutical lead compounds environmental behavior

Information Technology : Information Technology Store and Retrieve Molecular Structures and Properties Efficient Retrieval Critical Step Multi-million $ industry Pharmaceutical Industry $3-$5 million to bring a new drug to market Need to find accurate information Shorten time to market, minimize mistakes

High Throughput Screening : High Throughput Screening Test 10,000-100,000’s of compounds Robotics Individually Pfizer: 250,000 library Compact shelving Combinatorial Chemistry Parallel Cleverly prepared mixtures Recover most active compounds

CAMD Steps : CAMD Steps Determine Structure of Guest or Host Build a model of binding site Search databases for new guests (or hosts) Dock new guests and binding sites Predict binding constants or activity Synthesize guests or hosts

Acetylcholine Esterase : Acetylcholine Esterase Neurotransmitter recycling Design drug that acts like nicotinamide

Acetylcholine Esterase : Acetylcholine Esterase Brookhaven protein database Human disease- molecular biology databases SWISS-PROT OMIM GenBank MEDLINE

Structure Searches : Structure Searches 2D Substructure searches 3D Substructure searches 3D Conformationally flexible searches cfs

2D Substructure Searches : 2D Substructure Searches Functional groups Connectivity Halogen substituted aromatic and a carboxyl group

2D Substructure Searches : 2D Substructure Searches Query: Halogen substituted aromatic and a carboxyl group

3D Substructure Searches : 3D Substructure Searches Spatial Relationships Define ranges for distances and angles Stored conformation usually lowest energy

3D Structural Databases : 3D Structural Databases Compendium of Medicinal Chemistry 6,000 (ISIS) NCI-3D Chemotherapy Screening 250,000 (WWW) Cambridge Structural Database X-ray 128,000 (Quest, ISIS) CRC Properties of Organic Compounds 28,000 (Windows, Microsoft Access)

Conformationally Flexible Searches : Conformationally Flexible Searches Rotate around all freely rotatable bonds Many conformations Low energy penalty Get many more hits Guests adapt to hosts and Hosts adapt to guests

Guest-Host Chemistry : Guest-Host Chemistry

Binding Site Model : Binding Site Model Using experimental binding constants Build interaction model of host binding site Use 3D database searching to find other good guests

Nizatidine-Guests : Nizatidine-Guests

Binding Model : Binding Model

Pharmacophore : Pharmacophore

Computer Aided Molecular Design : Computer Aided Molecular Design Quantitative Structure Activity Relationships- QSAR Quantitative Structure Property Relationships- QSPR

Structure-Activity Relationships : Structure-Activity Relationships Determine binding constants NMR Fluorescence UV/Visible Titration Calorimetry HPLC

QSAR : QSAR Uncover important factors in chemical reactivity Based on Hammett Relationships in Organic Chemistry Medicinal Chemistry Guest-Host Chemistry Environmental Chemistry

pKa Substituted Benzoic Acids : pKa Substituted Benzoic Acids log Ka - log KaH = s K aH is the reference compound- unsubstituted

Hammett s Constants : Hammett s Constants

Growth Inhibition for Hamster Ovary Cancer Cells : Growth Inhibition for Hamster Ovary Cancer Cells -NO2 -NH3+

QSAR Descriptors and Datasets : QSAR Descriptors and Datasets MedChem Project- Pomona College Leo Hansch WWW version Curriculum materials

Reaction Databases : Reaction Databases 600,000 chemical reactions Synthetic routes ChemInform - Reacts Access by substructure and bond rearrangments Most used database by students

Information Rich Curriculum : Information Rich Curriculum Independent and Creative Gather Information Efficiently Judge the Quality of the Information Use information to Form Policies and Make Decisions

Information Rich Curriculum : Information Rich Curriculum Massive amount of information Database technology Central to mission of the course Students are active participants Gathering and Assessing Quality Simulation