Organic Chemistry

Section 30.9 Quantitative Structure–Activity Relationships (QSAR) 1221

30.9 Quantitative Structure–Activity

Relationships (QSAR)

The enormous cost involved in synthesizing and testing thousands of modified com-

pounds in an attempt to find an active drug led scientists to develop a more rational

approach—called rational drug design—to the design of biologically active mole-

cules. They realized that if a physical or chemical property of a series of compounds

could be correlated with biological activity, they would know what property of the

drug was related to that particular activity. Armed with this knowledge, scientists

could design compounds that would have a good chance of exhibiting the desired

activity. This strategy would be a great improvement over the random approach to

molecular modification that traditionally had been employed.

The first hint that a physical property of a drug could be related to biological activ-

ity appeared almost 100 years ago when scientists recognized that chloroform

diethyl ether, cyclopropane, and nitrous oxide were all useful general

anesthetics. Clearly, the chemical structures of these diverse compounds could not ac-

count for their similar pharmacological effects. Instead, some physical property must

explain the similarity of their biological activities.

In the early 1960s, Corwin Hansch postulated that the biological activityof a drug

depended on two processes. The first is distribution: A drug must be able to get from

the point where it enters the body to the receptor where it exerts its effect. For exam-

ple, an anesthetic must be able to cross the aqueous milieu (blood) and penetrate the

lipid barrier of nerve cell membranes. The second process is binding: When a drug

reaches its receptor, it must interact properly with it.

Chloroform, diethyl ether, cyclopropane, and nitrous oxide were each put into

a mixture of 1-octanol and water. 1-Octanol was chosen as the nonpolar solvent because,

(CHCl 3 ), (N 2 O)

Corwin H. Hanschwas born in

North Dakota in 1918. He received a

B.S. from the University of Illinois

and a Ph.D. from New York

University. He has been a professor

of chemistry at Pomona College

since 1946.

transimination

with E−(CH 2 ) 4 NH 2

E

N

H

HC H

O

(CH 2 ) 4

N +

H

N +

H

+

N

+H

N

E

CH 2 CH H

O

(CH 2 ) 4

+

NH

HC

N

O

C

O

−O−OOCH 2

R = P

O CH 2 C O−

CH 2 C C O− NH 2

HC

N

O

Cl CH 2 C C O−

BH

H Cl−

B−

−O C C

O

NH 2

H

O

H

O

inactivated enzyme

an elimination

reaction an amino acidα, β-unsaturated

an amine

linkage

CH 3 CH 3 CH 3

CH 3

R R R

R

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