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Computer Aided Molecular Design. A Strategy for Meeting the Challenges We Face. An Organized Guide. Build Chemical Insight Discover new molecules Predict their properties. Working at the Intersection. Structural Biology Biochemistry Medicinal Chemistry Toxicology Pharmacology

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computer aided molecular design

Computer Aided Molecular Design

A Strategy for Meeting the Challenges We Face

an organized guide
An Organized Guide
  • Build Chemical Insight
  • Discover new molecules
  • Predict their properties
working at the intersection
Working at the Intersection
  • Structural Biology
  • Biochemistry
  • Medicinal Chemistry
  • Toxicology
  • Pharmacology
  • Biophysical Chemistry
  • 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)
working at the intersection8
Working at the Intersection
  • Structural Biology
  • Biochemistry
  • Medicinal Chemistry
  • Toxicology
  • Pharmacology
  • Biophysical Chemistry
  • 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
principles11
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
molecular recognition
Molecular Recognition
  • Hydrogen bonding
  • Charge-charge interactions (salt bridges)
  • Dipole-dipole
  • p – p interactions (aromatic)
  • Hydrophobic (like dissolves like)
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
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 technology17
Information Technology
  • Store and Retrieve
  • Molecular Structures and Properties
  • Efficient Retrieval Critical Step
  • Multi-million $ industry
  • Pharmaceutical Industry
    • $830 million to bring a new drug to market
    • Need to find accurate information
    • Shorten time to market, minimize mistakes
slide18
CAMD
  • Computational techniques to guide chemical intuition
  • Design new hosts or guests
    • Enzyme inhibitors
    • Clinical analytical reagents
    • Catalysts
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
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 searches22
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
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
angiotensin converting enzyme
Angiotensin Converting Enzyme
  • Zn containing protease
  • Converts Angiotensin I
  • Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu
  • -> Angiotensin II
    • Raises blood pressure
    • Vascular constriction
    • Restricts flow to kidneys
    • Diminishing fluid loss

Losartan

computer aided molecular design27

Computer Aided Molecular Design

Quantitative Structure Activity Relationships- QSAR

Quantitative Structure Property Relationships- QSPR

introduction
Introduction
  • Uncover important factors in chemical reactivity
  • Based on Hammett Relationships in Organic Chemistry
  • Medicinal Chemistry
  • Guest-Host Chemistry
  • Environmental Chemistry
slide29
CAMD
  • 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
outline
Outline
  • Hammett Relationships
  • log P : Octanol-water partition coefficients
    • uses in Pharmaceutical Chemistry
    • uses in Environmental Chemistry
    • uses in Chromatography
  • Other Descriptors
  • Multivariate Least Squares
  • Nicotinic Agonists - Neurobiology
acetylcholine esterase
Acetylcholine Esterase
  • Neurotransmitter recycling
  • Design drug that acts like nicotine
acetylcholine esterase32
Acetylcholine Esterase
  • RCSB Protein Data Bank (PDB)
  • Human disease- molecular biology databases
    • SWISS-PROT
    • OMIM
    • GenBank
    • MEDLINE
hammett relationships
Hammett Relationships
  • pKa of benzoic acids
  • Effect of electron withdrawing and donating groups
  • based on rG = - RT ln Keq
pka substituted benzoic acids
pKa Substituted Benzoic Acids
  • log Ka - log KaH = 
  • K aH is the reference compound- unsubstituted
sigma rho plots
Sigma-rho plots
  • One application of QSPR
  • Activity = rs + constant
  • Y = mx + b
  • s: descriptor
  • r : slope
octanol water partition coefficients
Octanol-Water Partition Coefficients
  • P = C(octanol)

C(water)

  • log P

like rG = - RT ln Keq

  • Hydrophobic - hydrophilic character
  • P increases then more hydrophobic
isonarcotic activity of esters alcohols ketones and ethers with tadpoles
Isonarcotic Activity of Esters, Alcohols, Ketones, and Ethers with Tadpoles
  • log(1/C) = 0.869 log P + 1.242
      • n = 28 r = 0.965
  • subset of alcohols:

log(1/C) = 1.49 log P - 0.10 (log P)2 + 0.50

n = 10 r = 0.995

log p
log P

hydrophobic

benzene 2.13

pentanol 0.81

butylamine 0.85

n-propanol -0.23

pyridine 0.64

isopropanol -0.36

diethylamine 0.45

ethanol -.75

methanol -1.27

imidazole -0.08

phenylalanine -1.38

tetraethylammonium iodide -2.82

hydrophillic

alanine -2.85

estimating log p
Estimating log P
  • M (aq) –> M (octanol) PG = -RT ln P
  • M (aq) –> M (g) desolG(aq)
  • M (octanol) –> M (g) desolG(octanol)
  • PG = desolG(aq) – desolG(octanol)
  • PG = Fh2o - Foct
  • log P = – (1/2.303RT) Fh2o - Foct
    • 1/2.303RT = – 0.735
solvent solute interaction
Solvent-Solute Interaction
  • desolG(aq) = Fh2o
    • Free Energy of desolvation in water
    • desolG(aq) = -RT ln KHenry’s
  • desolG(octanol) = Foct
    • Free Energy of desolvation in octanol
descriptors
Descriptors
  • Molar Volume, Vm
  • Surface area
  • Rotatable Bonds, Rotbonds, b_rotN
  • Atomic Polarizability, Apol
    • Ease of distortion of electron clouds
    • sum of Van der Waals A coefficients
  • Molecular Refractivity, MR
    • size and polarizability
    • local non-lipophilic interactions
atomic polarizability apol
Atomic Polarizability, Apol
  • Atomic Polarizability
    • Ease of distortion of electron clouds
    • sum of Van der Waals A coefficients
molecular refractivity mr
Molecular Refractivity, MR
  • Molecular Refractivity, MR
    • size and polarizability
    • local non-lipophilic interactions
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