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

Ste

ric

Energ

y (

kca

l/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

Acetylcholine Esterase

RCSB Protein Data Bank (PDB)

Human disease- molecular biology databases» SWISS-PROT» OMIM» GenBank» MEDLINE

Acetylcholine Esterase

CH3 N

CH3

CH3

CH2CH2O C

O

CH3CH3 N

CH3

CH3

CH2CH2OH

O C

O

CH3 H+

OH2

+ ++

+ +

N

N+

H

Nicotine

Hammett Relationships

pKa of benzoic acids Effect of electron withdrawing and

donating groups based on rG = - RT ln Keq

pKa Substituted Benzoic Acids

log Ka - log KaH = K aH is the reference compound-

unsubstituted

-0.8

-0.6

-0.4-0.2

0

0.2

0.40.6

0.8

1

-1 -0.5 0 0.5 1

sigma

log Ka

O

O

H

R1

Hammett Constants

Group p m

-NH 2 -0.57 -0.09-OH -0.38 0.13-OCH3 -0.28 0.10-CH3 -0.14 -0.06-H 0 0-F 0.15 0.34-Cl 0.24 0.37-COOH 0.44 0.35-CN 0.70 0.62-NO2 0.81 0.71

Sigma-rho plots

One application of QSPR Activity = + constant Y = mx + b descriptor : slope

Growth Inhibition for Hamster Ovary Cancer Cells

N

(CH2CH2Cl)2R

y = -2.5 - 0.21

R2 = 0.97

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

1.5

-1 -0.5 0 0.5 1

log(1

/IC

50)

-NO2

-NH3+

Octanol-Water Partition Coefficients

P = C(octanol)

C(water) log P

like rG = - RT ln Keq

Hydrophobic - hydrophilic character

P increases then more hydrophobic

Octanol

H O2

QSAR and log P Isonarcotic Activity of Esters, Alcohols, Ketones,

and Ethers with Tadpoles

Compound log(1/C) log PCH3OH 0.30 -1.27C2H5OH 0.50 -0.75CH3COCH3 0.65 -0.73(CH3)2CHOH 0.90 -0.36(CH3)3COH 0.90 0.07CH3CH2CH2OH 1.00 -0.23CH3COOCH3 1.10 -0.38C2H5COCH3 1.10 -0.27HCOOC2H5 1.20 -0.38C2H5COC2H5 1.20 0.59(CH3)2C(C2H5)OH 1.20 0.59CH3(CH2)3OH 1.40 0.29(CH3)2CHCH2OH 1.40 0.16CH3COOC2H5 1.50 0.14C2H5COC2H5 1.50 0.31CH3(CH2)4OH 1.60 0.81CH3CH2CH2COCH3 1.70 0.31CH3COOCH2C2H5 2.00 0.66C2H5COOC2H5 2.00 0.66(CH3)2CHCOOC2H5 2.20 1.05

QSAR and log P Isonarcotic Activity of Esters, Alcohols, Ketones,

and Ethers with Tadpoles

y = 0.7315x + 1.2211

R2 = 0.7767

0

0.5

1

1.5

2

2.5

-2 -1 0 1 2log P

log

(1/C

) R = 0.881n = 20

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 + 0.50n = 10 r = 0.995

log Plog P

hydrophillic

hydrophobic

ethanol -.75

pentanol 0.81

isopropanol -0.36n-propanol -0.23

benzene 2.13

methanol -1.27

tetraethylammonium iodide -2.82

phenylalanine -1.38

alanine -2.85

pyridine 0.64

imidazole -0.08

diethylamine 0.45

butylamine 0.85

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

desolG(aq) = Fh2o

» Free Energy of desolvation in waterdesolG(aq) = -RT ln KHenry’s

desolG(octanol) = Foct

» Free Energy of desolvation in octanol

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» Ease of distortion of electron clouds» sum of Van der Waals A coefficients

EVdW,ij = - Arij6 +

Brij

12

Molecular Refractivity, MR

Molecular Refractivity, MR» size and polarizability» local non-lipophilic interactions

Lorentz-Lorentz equation:

MR = (n2 - 1)(n2 + 2)

MW

d

Group Additive Properties, GAPs

Substituent Volume (SA) MR Rot Bonds

-H 1.48 0.10 0 (reference) 0

-CH3 18.78 0.57 0.56 0

-CH2CH3 35.35 1.03 1.02 1

-CH2CH2CH3 51.99 1.5 1.55 2

-CH(CH3)2 51.33 1.5 1.53 1

-CH2CH2CH2CH3 68.63 1.96 2.13 3

-C(CH3)3 86.99 1.96 1.98 1

-C6H5 72.20 2.54 1.96 1 -F 7.05 0.10 0.14 0

-Cl 15.85 0.60 0.71 0