Drug Information Journal, Vol. 17, pp. 121-131. 1983 0092-8615/83 $3.00 + .

00
Printed in the USA. All rights reserved. 0 1983 Drug Information Association Inc.

QUANTUM MECHANICS IN DRUG

DESIGN: METHODS AND APPLICATIONS
B. BOYD,PHD
DONALD
Research Scientist
Lilly Research Laboratories
Indianapolis, Indiana

Quantum mechanics is especially useful in drug design when the mode of action of
the drug involves a chemical reaction. Some advantages as well as caveats about the
role of quantum mechanics in molecular modeling are reviewed.

Key Words: Computer-Assisted drug design; Molecular orbital calculations; Molecular

mechanics; Theoretical chemistry; 8-Lactam antibiotics

INTRODUCTION design and understanding of P-lactam anti-

biotics.
There are two main theoretical approach-
THIS PAPER is aimed at introducing the
es to studying the three-dimensional shape
laboratory medicinal chemist to some as-
and certain other physicochemical proper-
pects and terminology of theoretical com-
ties of biologically interesting molecules.
puter-assisted drug design. The paper is
One is molecular mechanics.'.2 The other
divided into two parts. The first part gives
method is quantum mechanics.
an overview of quantum mechanics, and,
Of the two approaches, the latter, quan-
in particular, a comparison of it to molecu-
tum mechanics, is older. The germinal mo-
lar mechanics. Some of the different quan-
lecular mechanics calculations were pub-
tum mechanical methods along with their
lished in the late 1 9 4 0 ~whereas
,~ quantum
strengths and weaknesses are briefly men-
mechanics has been applied to small mole-
tioned. No attempt will be made to go into
cules since the 1920s and to large, biologi-
the theory behind these methods because
cally interesting molecules since the early
the main point of interest to this audience
1950s. The research field of using quantum
is their utility. Likewise, no attempt will be
mechanics to study molecules of biologi-
made to review the literature on quantum
cal and pharmaceutical interest is mature
mechanics in drug design because it is al-
enough and large enough that the names
ready so large and rapidly growing. The
quantum biology and quantum phar-
second part briefly summarizes some of the
macology have been widely used since the
applications of quantum mechanics to the
late 1 9 6 0 ~ . ~ - "
One should not view quantum mechan-
This paper is based on an invited lecture at the Drug ics and molecular mechanics as competitive
Information Association Workshop on Computer in any way. They complement each other
Assisted Chemistry in Drug Design, February 20 to nicely. We therefore d o not advocate the
23, 1983, Philadelphia, Pennsylvania.
Reprint address: Dr Donald B. Boyd, Lilly Re-
sole use of quantum mechanics in molecular
search Laboratories, Eli Lilly and Company, Indian- modeling studies. In fact, there is a syner-
apolis, I N 46285. gistic interplay of the various approaches
121
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122 Donald B. Boyd

to computer-assisted chemistry, including lecular mechanics calculations have been

quantum mechanics, molecular mechanics, finely tuned over the last decade.
computer graphics, quantitative structure-
activity relationship (QSAR) techniques,
ADVANTAGES OF QUANTUM
and data base management.
MECHANICS
One might wonder, why use quantum
ADVANTAGES OF MOLECULAR
mechanics at all? There are some very good
MECHANICS
reasons. One is that quantum mechanics is
Some advantages of a molecular mechani- relatively general. We can take a molecule
cal approach to molecular modeling as con- with just about any functional group of in-
trasted with a quantum mechanical one are terest and compute properties like energy,
considered first. Because of its conceptual equilibrium geometry, et cetera. For a typ-
simplicity, molecular mechanics is easier ical quantum mechanical calculation using
for the average chemist to understand. One one of the modern programs, all the user
does not have to bother with things like needs for input is a reasonable set of geo-
kinetic energy integrals, resonance inte- metrical data. On the other hand, one of
grals, exchange integrals, and so forth. One the most bothersome restrictions of molec-
thinks in terms of Hook's law force con- ular mechanics is that, in addition to the
stants, natural bond lengths and bond an- geometrical data, every functional group
gles, van der Waals radii of atoms, et cet- needs its own unique set of parameters, and
era.'.3 no molecular mechanics program has good
In terms of speed, the three-dimension- values for all the parameters that one is
al structure of molecules can be determined likely to need.
with three orders of magnitude less compu- A second advantage of quantum me-
ter time by molecular mechanics than by chanics is that we can compute more prop-
quantum mechanics. Interactive computing erties. As mentioned, molecular mechanics
is becoming more popular. The user wants gives conformational energies and excellent
to see some results immediately. Molecu- bond lengths and bond angles in cases where
lar mechanics is ideally suited to this en- the force field is adequately parameterized.
vironment, and one would suspect that the In addition, some molecular mechanics
number of users of molecular mechanics programs like MM2 give a dipole moment
has been growing at a faster rate than the estimated from empirical bond moments
number of users of quantum mechanics. and also an empirically derived heat of for-
If all we need to know are the preferred mation. On the other hand, a quantum
conformations of some large molecule and mechanical program like MIND0/3 or
the relative energies of these conformers, MNDO gives all these properties, and many
then once again, molecular mechanics is the more.
method of choice. Quite commonly all the With quantum mechanics we can com-
chemist wants to have is a realistic picture pute electronic properties, such as charge
of a molecule in three dimensions. This can distributions. The charges on particular
help visualization of the steric and shape atoms can give us clues about reactive sites
properties of a drug. in a molecule or about how one molecule
Finally, there is the matter of accuracy. will interact electrostatically with another
A molecular mechanics program3 like molecule.
MM2 can often give structural information The quantum chemical calculations also
as good as one could obtain experimental- yield orbital energies and ionization poten-
ly. This accuracy is achievable because the tials. One example of use of the latter is the
empirical parameters which enter the mo- work of Domelsmith, et al.9 They reported

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Drug Design
that human psychotomimetic activity of
amphetamine analogs is related to their ion-
ization potential. Correlations were found
because the orbital energies reflect the elec-
tron-richness of the aromatic ring.
Quantum mechanics is especially well
suited to deal with transition states and
electronically excited molecules. Sometimes
in drug design one is attempting to arrive
at a transition state inhibitor. That is, one
wants a molecule that is structurally and
electronically similar to a transition state
formed by an enzyme’s natural substrate.
The enzyme will mistake the analog for its
substrate and be inhibited when the analog
is able to bind at the active site more strong-
ly than the substrate can. Quantum me-
chanics, especially at the more sophisticat-
ed levels, can provide good representations
of the structural and electronic properties
of even short-lived species.
Finally, there is the matter of theoretical
rigor. Quantum mechanics is firmly based on
the Schrodinger equation. As stated in Burk-
ert and Allinger’s Molecular mechanic^,^
For calculating molecular properties, quantum
mechanics seems to be the obvious tool t o use.
Calculations that d o not use the Schrodinger
equation are acceptable only t o the extent that
they reproduce the results of high level quantum
mechanical calculations.
Some theoretical purists like to emphasize
that molecular mechanics is nothing more
than a fancy interpolative scheme. How-
ever, other theoreticians feel that there is
a physical justification behind the seeming-
ly ad hoc prescription of the molecular
mechanics formalism. What really matters,
of course, is whether the results are useful.
In that light, both quantum mechanics and
molecular mechanics can provide informa-
tion helpful to drug design.
SYNERGISM
The two approaches - quantum mechanics
and molecular mechanics -can even help
each other. Consider the common situation
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123
where one wants t o obtain accurate infor-
mation about some large drug molecules.
Not infrequently the molecules are much
too big to determine every structural variable
by ab initio calculations, that is, quantum
mechanical calculations based only on first
principles and without empiricism.
One can start out by doing ab initio cal-
culations on simple model structures that
contain the functional groups of interest.
This will give the optimized internal geo-
metry, i.e., the equilibrium bond lengths,
bond angles, and torsional angles. Addi-
tionally, information is obtained about
charges on atoms and about the potential
energy surface, such as how much energy
is required to deform or twist a bond.
With this information in hand, one can
next do molecular mechanics calculations
on the model structures and empirically ad-
just the force constant parameters until the
ab initio results are adequately reproduced.
The collection of parameters and empirical
energy functions, called the “force field,”
can then be used to determine the three-
dimensional structure of conformations of
the large molecules. The speed of these mo-
lecular mechanics calculations allows the
whole grid of conformational space to be
spanned if one desires. Finally, the atomic
coordinates for selected conformations of
special interest can be fed into a quantum
mechanical program to obtain the informa-
tion that one was after to begin with.
QUANTUM MECHANICAL METHODS
There is a plethora of quantum mechanical
programs available to the scientific com-
munity. Fortunately, most of these can be
obtained for just a nominal charge from the
Quantum Chemistry Program Exchange
(QCPE) at Indiana University.’
At the Lilly Research Laboratories,’O the
semiempirical molecular orbital (MO) pro-
grams that we have found useful from time
to time include EHT (Extended Huckel
theory), CND0/2 (complete neglect of dif-
ferential overlap), INDO (intermediate neg-
124 Donald B. Boyd

lect of differeptial overlap); CND0/2D and Molecular properties can be computed

INDO/D (where the normal calculation is
followed by a deorthogonalization step and
subsequent Mulliken population analysis,”
CNDO/S (parameterized for electron spec-
troscopy), MIND0/3 (modified intermedi-
ate neglect of differential overlap), and
MNDO (modified neglect of diatomic dif-
ferential overlap).
On the ab initio side, HONDOS and the
GAUSSIAN programs are very useful. These
can use basis sets like STO-3G, 4-31G, et
cetera, that are frequently seen mentioned
in the l i t e r a t ~ r e .The
~ . ~basis set is the col-
lection of mathematical functions used to
describe the atomic orbitals.
How d o you select one of these MO pro-
grams? Essentially, you need to balance your
need for accuracy with how much you are
willing to pay. Some methods are compared
in Figure 1 regarding their speed and relative
error in predicting the properties listed. The
comparison is entirely qualitative and gen-
eralized over a number of molecule^.'^-^^
by ab initio methods, but a great deal of
computer time will be needed, and the size
of the model structures may have to be
limited. An ab initio calculation can con-
sume ten-fold or more computer time than
a semiempirical one. In order to save time,
some theoreticians who d o ab initio calcu-
lations use such a “bare bones” basis set
that the predictions may be even less reliable
than semiempirical ones. Thus, using an ab
initio method does not automatically insure
reliability.
At the other extreme, the semiempirical
method Extended Huckel is very fast. It
can handle huge molecules. It is not very
reliable for some problems, but is often
fine for constructing orbital correlation
diagrams, such as in determining whether
a reaction is allowed under the Woodward-
Hoffmann rules.
PCILO (perturbative configuration in-
teraction using localized orbitals) is a quan-
tum mechanical method, but not an MO

1 EH

CNDO12
INDO

(PCILO)
MINDO13
Calculated
Properties
Relative Total Energies
Orbital Energies
lonization Potentials
Charges
Dipole Moments
Geometries

PRDDO
MNDO
VRDDO
AB INlTlO
_ _ ~
7

Relative CPU Time Per Geometry

FIGURE 1. Comparison of some popular molecular orbital methods and PClLO in terms
of relative central processing unit computing time and relative error in predicted proper-
ties. Scales are arbitrary. Parentheses around PClLO take note of the fact that it Is not
an MO method and cannot be used to compute all the properties listed.

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Drug Design
method. PCILO is fast and can sometimes
give equilibrium bond lengths and bond
angles about as accurately as MIND0/3.
PCILO is used mainly for conformational
studies, but the publicly available programs
for this method are not especially user-
friendly and sometimes predict anoma-
lous hydrogen-bonded conformations to be
stable.
PRDDO and VRDDO stand for “partial
retention” and “variable retention” of dia-
tomic differential overlap, respectively,
which means that some two-electron and
electron-nuclear attraction integrals are dis-
carded. They are “approximate ab initio”
methods. This may be a confusing combi-
nation of terms. They are ab initio in the
sense that there are no parameters empiri-
cally fit to experiment. But they are ap-
proximate because some integrals are left
out or approximated. The methods are
fairly accurate, but have not become too
widely used because the authors have not
made them available through QCPE.
CND0/2, INDO, MIND0/3, and
MNDO are readily available from QCPE
and, depending on the problem at hand,
represent appropriate compromises between
speed and accuracy. MINDO/3 and MNDO
can be very useful for predicting properties
such as internal geometries, gas-phase reac-
tion energies, charges, vibrational frequen-
cies, dipole moments, ionization potentials,
and transition state structures.
Unfortunately, most MO methods are
subject to some systematic shortcomings.
For instance, neither MIND0/3 nor MNDO
is any good at treating hydrogen bond-
ing.7.13.15-17
Recently, however, a new ver-
sion of MINDO/3 has been published which
addresses this problem.18 Another systema-
tic problem with MIND0/3 and MNDO is
that barriers to internal rotation come out
somewhat low .19.20 One problem with the
CND0/2 and INDO methods is that they
overestimate attractive interactions between
atoms, so that hydrogen bonds and non-
bonded contacts are predicted to have equil-
ibrium distances shorter than those observed
e~perimentally.~’-~~
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125
QUALITY ASSURANCE
In order to avoid some of the systematic
problems, users of the quantum mechanical
methods are encouraged to keep the follow-
ing principles’ in mind. These points may
seem self-evident, but they are important
in order to avoid misleading computational
results.
1. Test the theoretical method on some
simple known cases related to the prob-
lem at hand. Before expending a lot of
time and effort, you should see whether
the method is giving reasonable results
where experimental data are available
for comparison.
2. Use more than one theoretical procedure
if applicable to your problem. This will
help you spot systematic errors produced
by some of the methods.
3. Study a series of related molecules.
Unavoidable systematic errors can some-
times be taken into account if you use
the predicted results for comparison
among themselves. In other words, rela-
tive values are more meaningful than ab-
solute values.
4. Consider whether any new effects that
are predicted agree with chemical intui-
tion. For instance, you may think you
are discovering a new chemical princi-
ple, when, in fact, you are seeing the ar-
tifact of one theoretical method.
5 . Consult the literature. Ideally, all re-
searchers should be fully familiar with
what has already been published. This
would help them avoid repeating other
people’s unsuccessful endeavors. How-
ever, it is difficult enough for the spe-
cialist to keep up with computational
chemistry and even more difficult for
the laboratory scientist who only occa-
sionally uses a theoretical method t o be
aware of its shortcomings. The literature
is sprinkled with examples where the
same computational experiments are
duplicated by independent groups. This
situation stems in part from the fact that
it is now often easier to d o a theoretical
126
calculation yourself than to retrieve from
the literature a previous calculation on
the same problem.
Those who are interested in the more
pragmatic aspects of the methods just dis-
cussed are urged to attend one of the annual
workshops that are held by the Quantum
Chemistry Program Exchange at Indiana
University.’ Those workshops provide ex-
cellent “hands-on” experience with the pop-
ular methods.
APPLICATIONS
Having discussed some general aspects
about the quantum chemical methods, at-
tention will next focus on one specific area
of application. This application is note-
worthy because of its success in illuminat-
ing the biological activity of a significant
class of drugs, the cephalosporin antibiotics.
The application is also of interest because
theoretical techniques provided insight into
the transition state structure of a reaction
mechanism that is clearly pertinent to drug
design.24
Some well known examples of cephalo-
sporins are shown in Figure 2. Note that
the structures differ by the substituents at
the 3 and 7 positions on the cephem nucleus.
Compared to drugs in other therapeutic
areas, much is known about the biological
and biochemical mode of action of ceph-
alosporins and other 0-lactam antibi-
o t i c ~ . ~The
. ~ availability
~-~~ of this infor-
mation is invaluable to the application of
theoretical molecular modeling methods.
The P-lactam antibiotics act as acylat-
ing agents. We therefore need to examine
the hypothesis that the biological activity of
a cephalosporin is related to the reactivity
of the P-lactam ring. The reactivity, in turn,
may be related to how easy it is for a nucle-
ophile to appr0ac.h the vicinity of the P-
lactam carbonyl carbon. Furthermore, one
may suppose that the electron cloud above
and below this carbon through which the
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Donald B. Boyd
nucleophile must penetrate will be intimate-
ly linked via the enamine pi-electron system
to the substituent at the 3 position on the
cephem ring. We can set out to test this set
of hypotheses using quantum mechanical
computational techniques.
Specifically, we can use a model cephem
structure with different substituents at the
3 position; a hydroxide ion will suffice as a
model nucleophile. The calculations will
tell us about the energetics involved in the
approach of the two reactants in this model
rea~tion.~ The
’ energy change can be com-
puted by the C N D 0 / 2 molecular orbital
method. C N D 0 / 2 is well suited for this
problem because it reflects quite nicely the
electronic effects of substituents that are
transmitted throughout the molecule. Also,
C N D 0 / 2 is relatively fast and can handle
large model structures.
The change in energy brought about by
moving the nucleophile from infinity to
the optimized location near the P-lactam
ring is called the Transition State Energy
(TSE).32The more negative the TSE, the
easier it is for the nucleophile to react
with the P-lactam. The TSEs range from
about - 128 to - 142 kcal/mole. The mag-
nitude does not matter. What is important
are the relative values for different substitu-
ents. As the 3-substituent makes the 0-
lactam more reactive, the TSE becomes
more negative.
As seen in Figure 3, the TSEs correlate
with in vitro antibacterial activity against
some less resistant gram-negative patho-
gens. The parabolic.natut-e of the curve
arises because when the quantum mechan-
ically predicted reactivity is low, then the
compound does not acylate the bacterial
enzymes well and the antibacterial activity
is low. On the other hand, when the calcu-
lated reactivity is too high, then the com-
pound has stability problems and decom-
poses before having a chance to exert its
activity. Not many compounds have been
made at the high TSE end of the scale be-
cause the compounds are difficult to obtain
owing to their lack of stability. The opti-
Drug Design 127

Y H H
R c
- -N Tf>
0 4’
o 5 R3
COOH
Name Ri R3
0
CEPHALOTHIN -CH2- 0- C- CH3
(1964)

CEPHALORIDINE -CH2- N(0)

(1968)
0
CEPHALOGLYCIN -CH,-O-C-CH,
(19701

CEPHALEXIN -CH3
(1971)

N= N, N-N
CEFAZOLIN NbN-CH, -CH2-S Xs& C H 3
(1973)
N-N
CEFAMANDOLE -CH,-S-(
N’
“N
(1978) OH
CH3

CEFACLOR -CI
(1979)

FIGURE 2. Structures of some cephalosporin antibiotics and the year they were intro-
duced into the United States market by Eli Lilly and Company.

mum biological activity is thus achieved in
the intermediate range on the TSE scale.
Regression analysis can be used t o ana-
lyze statistically the type of correlation seen
in Figure 3 . Irrespective of whether the
biological activity is expressed in terms of
MICs or logarithms of the reciprocal of the
MIC, satisfactory regression equations are
obtained.8.28These show that a quantum
mechanically derived index is able t o ex-
plain more than half of the variance in the
biological data for a rather complex pro-
cess, namely, the inhibition of bacterial cell
growth.
DISCUSSION AND CONCLUSION
In this molecular modeling study, one must
go beyond just looking at the three-dimen-
sional structure of the molecules and look
at the electronic properties which determine
the chemical reactivity. Conversely, the

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I28 Donald B. Boyd

70 I I I I I I I I I I I I I
-

:
60 -
-

30

1
20

“E
0

128 130 132 134 136 138 140

CONHZI
142
-Transition State Energy, kcal/mole
FIGURE 3. Antibacterial activity versus TSE. Activity is given as an average of gradient
piate minimum inhibitory concentrations (MIC) in pglml of a series of 7-(thien-2-ylacetyi)
cephalosporins agalnst Shigella sonnei, Escherichla coll, Klebslella pneumoniae, Entero-
bacter aerogenes, and Salmonella heidelberg. The substituents at position 3 of the cephem
nucleus are shown.

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Drug Design
shape of a P-lactam antibiotic structure can
be one of the important parameters when
comparing how well different 0-lactam
nuclei fit into an active Based on a
study of a heterogeneous set of 0-lactam
antibiotics in enzyme systems of limited rel-
evance to the lethal target enzymes, it has
been reported that goodness of fit is more
important than chemical r e a ~ t i v i t yHow-
.~~
ever, for a series of related structures where
molecular shape is invariant in the sterically
important regions, such as for the 3-substi-
tuted cephalosporins, chemical reactivity
becomes the dominant parameter affecting
antibacterial activity.
Quantum mechanical modeling for the
7-(thien-2-ylacetyl) cephalosporins offers
some unique advantages. Pervasive con-
cepts about the structure-activity relation-
ships of 0-lactam antibiotics suggest that
lipophilicity and vibrational spectroscopic
data should be useful predictors of antibac-
terial activity. However, octanol/water par-
tition coefficients have been measured at
pH 3 and 7 for these compounds, and they
do not show any correlation with the MICS.~
Also, 0-lactam carbonyl stretching frequen-
cies from ir spectra of 7-(thien-2-ylacetyl)
cephalosporins do not correlate significant-
ly with biological data.8
One other advantage of the quantum
mechanically derived molecular properties
can be pointed out. That is that from the
beginning, a specific step in the mode of ac-
tion is being modeled by the calculations.
Thus, when a correlation is found, we know
how to interpret it. On the other hand,
arbitrary assemblages of molecular features
or physicochemical properties often give
nice correlations with a particular biological
activity, but it is sometimes difficult to
know what the correlation signifies.
Before concluding, two other experimen-
tal observables that correlate with TSEs
and closely related quantum mechanical in-
dices, such as charge d i s t r i b ~ t i o nshould
,~~
be pointed out. One of these is the carbon-
13 chemical shift difference for carbons 3
and 4 of the cephem ring. Apparently 3-sub-
stituents that give better activity also cause
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129
more electron density to shift to C(3) and
away from C(4). The chemical shift differ-
ence correlates linearly with TSE.36 The
second experimental observable that corre-
lates with TSEs is the rate of alkaline hy-
drolysis (near pH 10) of the 0-lactam ring
of 7-(thien-2-ylacetyl) cephalosporins.
8,35.37 As one would expect, those 3-sub-
stituted cephalosporins that hydrolyze faster
have higher TSEs. An example of a correla-
tion between hydrolysis rate of cephalo-
sporins and the electron density on the 0-
lactam carbonyl oxygen is shown in Fig-
ure 4.
Several pieces of experimental and the-
oretical data thus fit together in a very log-
ical manner. It is safe to conclude that the
quantum mechanical calculations are giving
meaningful results. In contrast to QSAR
parameters often used in drug design, the
quantum mechanically derived molecular
parameters have the attribute that they can
be obtained regardless of whether the com-
pound has been previously synthesized and
regardless of whether the substituent is one
that appears in one of the familiar tables
of QSAR parameters.
PROGNOSTICATION
Drug design is becoming more sophisticat-
ed. More is being learned about the bio-
chemical mode of action of drugs. X-ray
crystallography is producing the three-di-
mensional structure of more potential tar-
gets of drug action. In this environment,
quantum mechanics will become increas-
ingly important as a tool for modeling the
drug-receptor interactions and other chemi-
cal events, such as metabolic transforma-
tions, that occur when a drug elicits a bio-
logical response. The word tool needs to be
emphasized. Quantum mechanics will not
displace any of the other important compu-
tational tools of drug design. The bottom
line of drug design is still (a) synthesizing
the compound and (b)testing the biological
activity. However, quantum mechanics will
hopefully help us reach this goal with more
efficiency and greater understanding.
130 Donald B. Boyd

-3.1

1
-3.6

i
-w
0
-4.1
1
-4.6

CH3
-5.1 I i 1 ~ i 1 1 ~ 1 1 1 ~ 1 1

-0.353 - 0.349 - 0.345 - 0.341

Q (091, e
FIGURE 4. Regression line for the relationship between rate of alkaline hydrolysis of
7-(thien-2-ylacetyl) cephaiosporins and CNDOlPD net atomic charge on the 0-lac-
tam carbonyl oxygen of model cephem structures. The substituents at position 3 of the
cephem nucleus are shown.

REFERENCES 6. Richards WG: Quantum Pharmacology. Woburn,

1. Boyd DB and Lipkowitz KB: Molecular mechan-
ics: The method and its underlying philosophy.
J Chem Educ 1982; 59: 269-274.
2. Lipkowitz KB and Boyd DB: Abstracts of Molecu-
lar Mechanics Symposium, Indiana University-
Purdue University at Indianapolis, Indianapolis,
IN. June 23-24, 1983.
3. Burkert U and Allinger NL: Molecular Mechanics,
ACS Monograph 177. American Chemical Society,
Washington, DC,1982, and references cited there-
in.
4. Pullman B and Pullman A: Quantum Biochem-
istry. New York, Wiley-Interscience, 1963.
5. Bergmann ED and Pullman B: Molecular and
Quantum Pharmacology. Dordrecht, Holland; D.
Reidel; 1974.
MA, Butterworths, 1977.
7. Boyd DB: Notes on CNDO, INDO, MINDO, and
MNDO. Quantum Chemistry Program Exchange
Workshop on Practical Aspects of Quantum Chern-
istry, Indiana University, Bloomington, IN, June
21-26, 1981, and references cited therein.
8. Boyd DB: Theoretical and physicochemical studies
on P-lactam antibiotics, RB Morin and M Gor-
man (eds): Chemistry and Bio1og.y of &Lacram
Antibiotics. New York, Academic Press, 1982 vol
I , chap 5 , pp 437-545, and references cited therein.
9. Domelsmith LN, Eaton TA, Houk KN, et a1
Photoelectron spectra of psychotropic drugs. 6.
Relationships between physical properties and
pharmacological actions of amphetamine ana-
logues. J M e d C h e m 1981; 24: 1414-1421.
10. Boyd DB and Marsh MM: Computational chem-

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Drug Design
istry in the design of biologically active molecules
at Lilly. Abstracts of 183rd American Chemical
Society National Meeting, Las Vegas, Nevada,
March 28-April 2, 1982, COMP 9.
11. Boyd DB: Electron density and dipole moment
analysis of valence-electron wave functions. J Am
Chem SOC1972; 94: 64-70. Boyd DB: Electronic
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