Computer Aided Molecular Design - PowerPoint PPT Presentation

Computer aided molecular design l.jpg
Download
1 / 49

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

I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.

Download Presentation

Computer Aided Molecular Design

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Computer aided molecular design l.jpg

Computer Aided Molecular Design

A Strategy for Meeting the Challenges We Face


An organized guide l.jpg

An Organized Guide

  • Build Chemical Insight

  • Discover new molecules

  • Predict their properties


Working at the intersection l.jpg

Working at the Intersection

  • Structural Biology

  • Biochemistry

  • Medicinal Chemistry

  • Toxicology

  • Pharmacology

  • Biophysical Chemistry

  • Information Technology


Structural biology l.jpg

Structural Biology

  • Fastest growing area of biology

  • Protein and nucleic acid structure and function

  • How proteins control living processes


Medicinal chemistry l.jpg

Medicinal Chemistry

  • Organic Chemistry

  • Applied to disease

  • Example: design new enzyme inhibitor drugs

    • doxorubicin (anti-cancer)


Pharmacology l.jpg

Pharmacology

  • Biochemistry of Human Disease

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


New ideas from nature l.jpg

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 l.jpg

Working at the Intersection

  • Structural Biology

  • Biochemistry

  • Medicinal Chemistry

  • Toxicology

  • Pharmacology

  • Biophysical Chemistry

  • Information Technology


Principles l.jpg

Principles

  • Structure-Function Relationships

  • Binding

    • Step 1: Biochemical Mechanism

    • Step 2: Understand and control macromolecular binding


Binding l.jpg

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 l.jpg

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 l.jpg

Molecular Recognition

  • Hydrogen bonding

  • Charge-charge interactions (salt bridges)

  • Dipole-dipole

  • p – p interactions (aromatic)

  • Hydrophobic (like dissolves like)


Hosts cyclodextrin l.jpg

Hosts:  cyclodextrin


Hexasulfo calix 6 arenes l.jpg

Hexasulfo-calix[6]arenes


Molecular design l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

CAMD

  • Computational techniques to guide chemical intuition

  • Design new hosts or guests

    • Enzyme inhibitors

    • Clinical analytical reagents

    • Catalysts


Camd steps l.jpg

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 l.jpg

Structure Searches

  • 2D Substructure searches

  • 3D Substructure searches

  • 3D Conformationally flexible searches

    • cfs


2d substructure searches l.jpg

2D Substructure Searches

  • Functional groups

  • Connectivity

    • Halogen substituted aromatic and a carboxyl group


2d substructure searches22 l.jpg

2D Substructure Searches

  • Query:

    • Halogen substituted aromatic and a carboxyl group


3d substructure searches l.jpg

3D Substructure Searches

  • Spatial Relationships

  • Define ranges for distances and angles

  • Stored conformation

    • usually lowest energy


Conformationally flexible searches l.jpg

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


Conformationally flexible searches25 l.jpg

Conformationally Flexible Searches

  • Small energy penalty


Angiotensin converting enzyme l.jpg

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 l.jpg

Computer Aided Molecular Design

Quantitative Structure Activity Relationships- QSAR

Quantitative Structure Property Relationships- QSPR


Introduction l.jpg

Introduction

  • Uncover important factors in chemical reactivity

  • Based on Hammett Relationships in Organic Chemistry

  • Medicinal Chemistry

  • Guest-Host Chemistry

  • Environmental Chemistry


Slide29 l.jpg

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 l.jpg

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 l.jpg

Acetylcholine Esterase

  • Neurotransmitter recycling

  • Design drug that acts like nicotine


Acetylcholine esterase32 l.jpg

Acetylcholine Esterase

  • RCSB Protein Data Bank (PDB)

  • Human disease- molecular biology databases

    • SWISS-PROT

    • OMIM

    • GenBank

    • MEDLINE


Acetylcholine esterase33 l.jpg

Acetylcholine Esterase

+

+

Nicotine


Hammett relationships l.jpg

Hammett Relationships

  • pKa of benzoic acids

  • Effect of electron withdrawing and donating groups

  • based on rG = - RT ln Keq


Pka substituted benzoic acids l.jpg

pKa Substituted Benzoic Acids

  • log Ka - log KaH = 

  • K aH is the reference compound- unsubstituted


Hammett constants l.jpg

Hammett  Constants


Sigma rho plots l.jpg

Sigma-rho plots

  • One application of QSPR

  • Activity = rs + constant

  • Y = mx + b

  • s: descriptor

  • r : slope


Growth inhibition for hamster ovary cancer cells l.jpg

Growth Inhibition for Hamster Ovary Cancer Cells

-NH3+

-NO2


Octanol water partition coefficients l.jpg

Octanol-Water Partition Coefficients

  • P = C(octanol)

    C(water)

  • log P

    like rG = - RT ln Keq

  • Hydrophobic - hydrophilic character

  • P increases then more hydrophobic


Qsar and log p isonarcotic activity of esters alcohols ketones and ethers with tadpoles l.jpg

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


Qsar and log p isonarcotic activity of esters alcohols ketones and ethers with tadpoles41 l.jpg

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


Isonarcotic activity of esters alcohols ketones and ethers with tadpoles l.jpg

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 l.jpg

    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 l.jpg

    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 l.jpg

    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 l.jpg

    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 l.jpg

    Atomic Polarizability, Apol

    • Atomic Polarizability

      • Ease of distortion of electron clouds

      • sum of Van der Waals A coefficients


    Molecular refractivity mr l.jpg

    Molecular Refractivity, MR

    • Molecular Refractivity, MR

      • size and polarizability

      • local non-lipophilic interactions


    Group additive properties gaps l.jpg

    Group Additive Properties, GAPs


  • Login