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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 l.jpg

Computer Aided Molecular Design

A Strategy for Meeting the Challenges We Face


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An Organized Guide

  • Build Chemical Insight

  • Discover new molecules

  • Predict their properties


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Working at the Intersection

  • Structural Biology

  • Biochemistry

  • Medicinal Chemistry

  • Toxicology

  • Pharmacology

  • Biophysical Chemistry

  • Information Technology


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Structural Biology

  • Fastest growing area of biology

  • Protein and nucleic acid structure and function

  • How proteins control living processes


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Medicinal Chemistry

  • Organic Chemistry

  • Applied to disease

  • Example: design new enzyme inhibitor drugs

    • doxorubicin (anti-cancer)


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Pharmacology

  • Biochemistry of Human Disease

  • Different from Pharmacy: distribution of pharmaceuticals, drug delivery systems


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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)


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Working at the Intersection

  • Structural Biology

  • Biochemistry

  • Medicinal Chemistry

  • Toxicology

  • Pharmacology

  • Biophysical Chemistry

  • Information Technology


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Principles

  • Structure-Function Relationships

  • Binding

    • Step 1: Biochemical Mechanism

    • Step 2: Understand and control macromolecular binding


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Binding

  • Binding interactions are how nature controls processes in living cells

  • Enzyme-substrate binding leads to catalysis

  • Protein-nucleic acid binding controls protein synthesis


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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


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Molecular Recognition

  • Hydrogen bonding

  • Charge-charge interactions (salt bridges)

  • Dipole-dipole

  • p – p interactions (aromatic)

  • Hydrophobic (like dissolves like)


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Hosts:  cyclodextrin



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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


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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


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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


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CAMD

  • Computational techniques to guide chemical intuition

  • Design new hosts or guests

    • Enzyme inhibitors

    • Clinical analytical reagents

    • Catalysts


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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


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Structure Searches

  • 2D Substructure searches

  • 3D Substructure searches

  • 3D Conformationally flexible searches

    • cfs


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2D Substructure Searches

  • Functional groups

  • Connectivity

    • Halogen substituted aromatic and a carboxyl group


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2D Substructure Searches

  • Query:

    • Halogen substituted aromatic and a carboxyl group


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3D Substructure Searches

  • Spatial Relationships

  • Define ranges for distances and angles

  • Stored conformation

    • usually lowest energy


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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



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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


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Computer Aided Molecular Design

Quantitative Structure Activity Relationships- QSAR

Quantitative Structure Property Relationships- QSPR


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Introduction

  • Uncover important factors in chemical reactivity

  • Based on Hammett Relationships in Organic Chemistry

  • Medicinal Chemistry

  • Guest-Host Chemistry

  • Environmental Chemistry


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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


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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


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Acetylcholine Esterase

  • Neurotransmitter recycling

  • Design drug that acts like nicotine


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Acetylcholine Esterase

  • RCSB Protein Data Bank (PDB)

  • Human disease- molecular biology databases

    • SWISS-PROT

    • OMIM

    • GenBank

    • MEDLINE



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Hammett Relationships

  • pKa of benzoic acids

  • Effect of electron withdrawing and donating groups

  • based on rG = - RT ln Keq


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pKa Substituted Benzoic Acids

  • log Ka - log KaH = 

  • K aH is the reference compound- unsubstituted


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Hammett  Constants


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Sigma-rho plots

  • One application of QSPR

  • Activity = rs + constant

  • Y = mx + b

  • s: descriptor

  • r : slope



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Octanol-Water Partition Coefficients

  • P = C(octanol)

    C(water)

  • log P

    like rG = - RT ln Keq

  • Hydrophobic - hydrophilic character

  • P increases then more hydrophobic


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QSAR and log P Isonarcotic Activity of Esters, Alcohols, Ketones, and Ethers with Tadpoles


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QSAR and log P Isonarcotic Activity of Esters, Alcohols, Ketones, and Ethers with Tadpoles


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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


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    log P Ethers with Tadpoles

    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


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    Estimating log P Ethers with Tadpoles

    • 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 l.jpg
    Solvent-Solute Interaction Ethers with Tadpoles

    • desolG(aq) = Fh2o

      • Free Energy of desolvation in water

      • desolG(aq) = -RT ln KHenry’s

    • desolG(octanol) = Foct

      • Free Energy of desolvation in octanol


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    Descriptors Ethers with Tadpoles

    • 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


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    Atomic Polarizability, Apol Ethers with Tadpoles

    • Atomic Polarizability

      • Ease of distortion of electron clouds

      • sum of Van der Waals A coefficients


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    Molecular Refractivity, MR Ethers with Tadpoles

    • Molecular Refractivity, MR

      • size and polarizability

      • local non-lipophilic interactions


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    Group Additive Properties, GAPs Ethers with Tadpoles


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