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 Biophysical Chemistry Information Technology

Structural Biology Fastest growing

area of biology Protein and nucleic

acid structure and function

How proteins control living processes

Medicinal Chemistry Organic Chemistry Applied to disease Example: design

new enzyme inhibitor drugs

– doxorubicin (anti-cancer)

Pharmacology Biochemistry of Human Disease

Different from Pharmacy: distribution of pharmaceuticals, drug delivery systems

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 Intersection Structural Biology Biochemistry Medicinal Chemistry Toxicology Pharmacology Biophysical Chemistry Information Technology

Principles Structure-Function Relationships Binding

» Step 1: Biochemical Mechanism» Step 2: Understand and control

macromolecular 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 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 RecognitionHydrogen bonding

•Charge-charge interactions (salt bridges)•Dipole-dipole –interactions (aromatic)• Hydrophobic (like dissolves like)

H

Hosts: cyclodextrinO

HO

O

OH

OH

O

HO

O

HO

OH

O

HO

OHO

OH

O

HOO HO

OH

O HO

O

HO

HO

O

HO

O

OH

HO

O

HO

OOH

HO

Hexasulfo-calix[6]arenes

O

H

O

H

O

H

O

H

O

H

O

H

S

S

S

S

S

S

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

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 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 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

CAMD Computational techniques to guide

chemical intuition Design new hosts or guests

» Enzyme inhibitors» Clinical analytical reagents» Catalysts

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 2D Substructure searches 3D Substructure searches 3D Conformationally flexible searches

» cfs

2D Substructure Searches Functional groups Connectivity

» Halogen substituted aromatic and a carboxyl group

[

F

,

C

l

,

B

r

,

I

]

O

O

2D Substructure Searches Query:

» Halogen substituted aromatic and a carboxyl group

N

O

O

Cl

O

O

Cl

N

N

N

O

O

F

F

O

F

O

O

N

I

O

N

3D Substructure Searches Spatial

Relationships Define ranges for

distances and angles

Stored conformation» usually lowest energy

C

(

u

)

O

(

s

1

)

O

(

s

1

)

A

A

[

O

,

S

]

O

3.6 - 4.6 Å

3.3 - 4.3 Å

6.8 - 7.8 Å

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

O

Cl

H

O

Cl

H

3.2Å

4.3Å

Conformationally Flexible Searches

O

Cl

H

O

Cl

H

3.2Å

4.3Å

3603002401801206000

1

2

3

4

5

6

Dihedral angle

Ster

ic E

nerg

y (k

cal/m

ol)

Small energy penalty

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

NN

ClO

N N

N N

Losartan

Computer Aided Molecular Design

Quantitative Structure Activity Relationships- QSAR

Quantitative Structure Property Relationships- QSPR

Introduction

Uncover important factors in chemical reactivity

Based on Hammett Relationships in Organic Chemistry

Medicinal Chemistry Guest-Host Chemistry Environmental Chemistry

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

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 Neurotransmitter

recycling Design drug that

acts like nicotine