Computer-Based Molecular Design of Artificial Flavoring Agents - ACS

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Computers in Flavor and Fragrance Research Downloaded from pubs.acs.org by NORTH CAROLINA STATE UNIV on 12/25/17. For personal use only.

Computer-Based Molecular Design of Artificial Flavoring Agents A. J. HOPFINGER and D. E. WALTERS Searle Research and Development, Department of Medicinal Chemistry, Skokie, IL 60077

Computational chemistry methodology is f i n d i n g i n c r e a s i n g a p p l i c a t i o n t o the design of new f l a v o r i n g agents. This chapter surveys s e v e r a l u s e f u l techniques: l i n e a r free energy r e l a t i o n s h i p s , q u a n t i t a t i v e s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s , conformational a n a l y s i s , e l e c t r o n i c s t r u c t u r e c a l c u l a t i o n s , and statistical methods. A p p l i c a t i o n s t o the study of artificial sweeteners are described. I m p l i c i t to research i n the biochemical sciences, of which the food and f l a v o r i n d u s t r i e s are members, i s that b i o l o g i c a l response, BR, i s a f u n c t i o n of chemical s t r u c t u r e , CS. The goal i s to f i n d that CS (compound) which maximizes a d e s i r e d BR and, simultaneously, min imizes other BRs, e s p e c i a l l y those d i r e c t l y r e l a t i n g to t o x i c i t y . In p r a c t i c e , t h i s i n v o l v e s the synthesis and t e s t i n g of new chemical e n t i t i e s , and, u n f o r t u n a t e l y , i s governed to a l a r g e extent by chance. A p p l i c a t i o n of computer-based molecular modeling i s i n t e n d ed to reduce the chance component, and, thereby, to enhance design capabilities. The design f u n c t i o n r e s t s upon r e c o g n i t i o n and implementation of the r e l a t i o n s h i p s shown i n Figure 1. In part A we f o r m a l i z e that not only do a l l BRs map i n t o (depend upon) CS, but so do a l l p h y s i cochemical p r o p e r t i e s , PPs. Therefore, the CS can, from f u n c t i o n a l mapping, be considered the common node between the BRs and the PPs. Consequently, a unique f u n c t i o n , f , must e x i s t between each BR and the set of PP. T h i s i s defined in°part Β of Figure 1. The key assumption i n molecular design i s that i f a p a r t i c u l a r BR i s of i n t e r e s t , say BR^, then the corresponding f . holds f o r any CS. T h i s i s expressed i n part C of Figure 1 where CS denotes an a r b i t r a r y mth chemical s t r u c t u r e . The r e l i a b i l i t y of t h i s assump t i o n increases as the s t r u c t u r a l homology of the set of CS increases and, a l s o , as the mechanisms of a c t i o n to r e a l i z e BR^ over the [CS ] converge to commonality. This i s a formal explanation why q u a n t i t a t i v e s t r u c t u r e a c t i v i t y r e l a t i o n s h i p , QSAR, s t u d i e s are more s u c c e s s f u l when a p p l i e d to e x p l a i n i n v i t r o a c t i v i t y i n a set of con generic analogs, as opposed to i n v i v o a c t i v i t y f o r a set of s t r u c t u r a l l y d i v e r s e compounds. m

0097-6156/ 84/ 0261 -0019S06.00/ 0 © 1984 American Chemical Society


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COMPUTERS IN FLAVOR AND F R A G R A N C E RESEARCH

BRl»fl(PPlrPP2r

fPPk)

BR2-f2(PPlfPP2f

fPPk)

;

BRn-f (PPl»PP2»~-PPk) n

C

(BR ) =(f.(PPi,PP , 1

m

2

PPk))in

Figure 1. The i n t e r r e l a t i o n s h i p s between b i o l o g i c a l response (BR), chemical s t r u c t u r e (CS), and physicochemical p r o p e r t i e s (PP) that l a y the conceptual b a s i s f o r molecular design.

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HOPFINGER AND WALTERS

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Artificial Flavoring Agents

Methods


1.

A d d i t i v e Property Models The simplest r e p r e s e n t a t i o n of a molecule, with respect to computing physicochemical p r o p e r t i e s , i s to assume the property to be the sum of the property values of the i n d i v i d u a l c o n s t i t u e n t atoms, or groups of atoms, Extensive data bases (1,2) of atomic and group (fragment) property values have been compiled to f a c i l i t a t e implementation of t h i s model. The most notable physicochemical p r o p e r t i e s employed i n QSARs using an a d d i t i v e property model are: 1. l o g P, the water-octanol p a r t i t i o n c o e f f i c i e n t , ( 3 ) 2. σ, the Hammett constant,(4) 3. MR, molecular r e f r a c t i v i t y index,(5) 4. pk , i o n i z a t i o n constant,(6) and 5· E , the T a f t s t e r i c constant. (2) a

s

Log Ρ and MR are considered thermodynamic d e s c r i p t o r s , pK a combined thermodynamic and e l e c t r o n i c index, and σ an e l e c t r o n i c property index. Ε i s designed to account f o r s t e r i c e f f e c t s . C o r r e c t i o n s f o r n o n - a d d i t i v i t y , based upon the chemical bonding topology, have been suggested and used. These i n c l u d e p r o x i m i t y , bond type, r i n g , and group shape c o r r e c t i o n f e a t u r e s . (8-10) Molecular c o n n e c t i v i t y , ( 1 1 ) which i s based upon graph theory, (12) i s an e m p i r i c a l a l t e r n a t i v e to an a d d i t i v e model employing physicochemical p r o p e r t i e s . D e s c r i p t o r s d e r i v e d from the molecular connection t a b l e (chemical bonding topology) employing mathematical f u n c t i o n s are considered as p o t e n t i a l a c t i v i t y c o r r e l a t e s . As such, t h i s approach i s completely mathematical and has no obvious physicochemical b a s i s . I t s strength i s that c o r r e l a t i o n i n d i c e s can always be generated (provided one knows how to a s s i g n i n t r i n s i c r e l a t i v e weights to i n d i v i d u a l atom types). a

2.

Hansch A n a l y s i s The most s u c c e s s f u l , and the most o f t e n used, method to c o n s t r u c t a QSAR i s that of Hansch.(13) T h i s method employs multi-dimensional l i n e a r r e g r e s s i o n a n a l y s i s to c o r r e l a t e s t r u c t u r e to a c t i v i t y i n a c h e m i c a l l y congeneric set of compounds. The s t r u c t u r a l f e a t u r e s have been t r a d i t i o n a l l y d e r i v e d from a d d i t i v e property models. However, recent a p p l i c a t i o n s of Hansch A n a l y s i s recognize any and a l l molecular d e s c r i p t o r s as p o t e n t i a l c o r r e l a t e s to a c t i v i t y . ( 1 4 , 1 5 ) Prominent among t h i s l i n e of t h i n k i n g i s Hansch h i m s e l f who now f r e e l y uses i n d i c a t o r v a r i a b l e s as c o r r e l a t e s . ( 1 6 ) An i n d i c a t o r v a r i a b l e has a value of 1 i f some user-defined property i s present i n a compound and a value of zero i f the property i s absent. I t i s important to p o i n t out that Hansch A n a l y s i s i s based upon a b i o l o g i c a l a c t i o n model. By d e r i v i n g the general QSAR equation a s s o c i a t e d with the

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RESEARCH

a c t i o n model, i t i s p o s s i b l e to c o n c e p t u a l l y j u s t i f y the general usage of any molecular d e s c r i p t o r i n a c o r r e l a t i o n analysis.(17)


3.

Conformational A n a l y s i s A drawback to a d d i t i v e property models of molecular s t r u c t u r e i s that 3-dimensional molecular p r o p e r t i e s cannot be determined. However, i t i s c l e a r that conformation, or more g e n e r a l l y , molecular shape, can be an important f a c t o r i n expression o f b i o l o g i c a l a c t i v i t y . Thus, there i s a need to be a b l e to determine conformational/shape p r o p e r t i e s of molecules and to use these p r o p e r t i e s to develop a QSAR. There are two p r i n c i p a l methods of performing computational conformational analyses: Molecular mechanics(18-19) and quantum mechanics.(20) Molecular mechanics considères a molecule as a set of b a l l s (the atoms), coated with s t i c k i n g paste, connected by a s e t of s p r i n g s (the bonds) according to a p r e s c r i b e d s e t of valence angles. Quantum mechanics views the molecule as a s e t of n u c l e i i n space with e l e c t r o n s moving about the n u c l e i . The goal of a conformational a n a l y s i s i s to minimize the energy of the molecule as a f u n c t i o n of i t s geometry. The energy minimization can i n v o l v e d i f f e r e n t types and numbers of geometric degrees of freedom which i n c l u d e bond l e n g t h s , bond angles, and t o r s i o n a l bond r o t a t i o n angles. An o f t e n employed approximation, e s p e c i a l l y f o r l a r g e molecules, i s to hold the valence geometry constant and minimize the energy as a f u n c t i o n of only t o r s i o n a l bond r o t a t i o n s . The unproven, but reasonable, assumption i m p l i c i t to SARd i r e c t e d conformational s t u d i e s , both experimental and t h e o r e t i c a l , i s that one of the s t a b l e i n t r a m o l e c u l a r conformers i s the " a c t i v e " conformation. A d i f f i c u l t y to applying conformational data i n q u a n t i t a t i v e drug design i s s e l e c t i o n of conformational f e a t u r e s f o r QSAR development. Moreover, molecular shape p r o p e r t i e s a r e p r e f e r a b l e f e a t u r e s to have a v a i l a b l e i n design s t u d i e s . Conformation i s a component of shape. The p r o p e r t i e s of the atoms, most notably t h e i r " s i z e s , " comprise an a d d i t i o n a l set of f a c t o r s needed t o s p e c i f y molecular shape. Conformational f e a t u r e s have been used i n some s t r u c t u r e a c t i v i t y s t u d i e s . Some examples a r e : (1) an i n t e r a t o m i c d i s t a n c e w i t h i n a molecule,(21,22) (2) a s e t of i n t e r a t o m i c d i s t a n c e s w i t h i n a molecule,(23,24) (3) a s e t of atomic coordinates w i t h i n a molecule,(25,26) (4) a s e t of c r i t i c a l i n t e r m o l e c u l a r b i n d i n g distances.(27) Molecular shape p r o p e r t i e s , d e r i v e d from conformational i n v e s t i g a t i o n s , have a l s o been used to r a t i o n a l i z e commonality and d i v e r s i t y i n b i o l o g i c a l a c t i o n . These shape p r o p e r t i e s include: (1) molecular volume,(28) (2) molecular s u r f a c e area,(29)

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(3) s p a t i a l p o t e n t i a l surfaces of a molecule with respect to a t e s t species.(30,31) A very powerful t o o l of v i s u a l i z i n g three-dimensional molecular p r o p e r t i e s , i n c l u d i n g p o t e n t i a l s u r f a c e s , i s computer graphics.(32) Computer graphics i s p a r t i c u l a r l y u s e f u l i n the q u a l i t a t i v e comparison of two or more molecules. A general theory of q u a n t i t a t i v e l y comparing molecular shapes using common overlap s t e r i c volume(33-36) and, more r e c e n t l y , d e s c r i p t o r s derived from superimposed molecular p o t e n t i a l energy f i e l d s of p a i r s of molecules(37) has been derived and t e s t e d . T h i s theory allows a "marriage" between Hansch a n a l y s i s and conformational a n a l y s i s . 4.

E l e c t r o n i c Structure Calculations Molecular o r b i t a l theory provides e l e c t r o n i c , as w e l l as conformational, data f o r i n c l u s i o n i n QSAR development. E l e c t r o n i c p r o p e r t i e s of a molecule might, i n p a r t , c o n t r o l b i o l o g i c a l a c t i v i t y when chemical r e a c t i o n s are p a r t of the mechanism of b i o l o g i c a l a c t i o n . E l e c t r o n i c i n d i c e s should a l s o be considered i n modeling p h y s i c a l i n t e r a c t i o n s i n order to provide charge d i s t r i b u t i o n data f o r estimating binding energies. E l e c t r o n i c i n d i c e s o f t e n considered i n structure«-activity studies include; a) atomic charge d e n s i t i e s , b) bond, group, and/or molecular d i p o l e moments, c) o r b i t a l energy l e v e l s , e s p e c i a l l y the highest occupied molecular o r b i t a l , HOMO, lowest unoccupied molecular o r b i t a l , LUMO, and t h e i r d i f f e r e n c e , and d) o r b i t a l wavefunction c o e f f i c i e n t s . Several d i f f e r e n t molecular o r b i t a l methods have been used i n SAR i n v e s t i g a t i o n s . These i n c l u d e simple Huckel theory, HT,(38) extended Huckel theory, EHT,(39) CNDO,(40) NDD0,(41) MINDO/3,(42) and PCILO.(43) 5.

S t a t i s t i c a l Methods Multidimensional l i n e a r r e g r e s s i o n a n a l y s i s i s the most o f t e n employed s t a t i s t i c a l method f o r QSARs. T h i s p o p u l a r i t y i s coupled t o the acceptance o f the Hansch method f o r QSAR analyses. The techniques and p i t f a l l s of r e g r e s s i o n a n a l y s i s have been w e l l described.(44,45) Other s t a t i s t i c a l methods employed i n q u a n t i t a t i v e molecular design i n v e s t i g a t i o n s i n c l u d e d i s c r i m i n a n t a n a l y s i s , c l u s t e r a n a l y s i s , m u l t i p l e f a c t o r a n a l y s i s , and p a t t e r n r e c o g n i t i o n procedures.(46-48) P a t t e r n r e c o g n i t i o n may prove p a r t i c u l a r l y u s e f u l when the design o b j e c t i v e i s a complicated p r o f i l e of b i o l o g i c a l a c t i v i t i e s , as opposed to only a maximized potency and minimized t o x i c i t y . Gottman(49) and Schiffman(50) have used multidimensional s c a l i n g methods to e s t a b l i s h i n t e r r e l a t i o n s h i p s between p s y c h o l o g i c a l sensory p r o f i l e s and physicochemical p r o p e r t i e s of f l a v o r agents, e s p e c i a l l y sweeteners.

COMPUTERS IN FLAVOR AND F R A G R A N C E RESEARCH

24 Case Study A p p l i c a t i o n s


L - A s p a r t y l Dipeptide Sweeteners Iwamura(51) has i n v e s t i g a t e d the structure-sweetness r e l a t i o n s h i p i n four c l a s s e s of L - a s p a r t y l d i p e p t i d e s using l i n e a r f r e e energy d e s c r i p t o r s and multi-dimensional r e g r e s s i o n a n a l y s i s . In essence, the Hansch methodology was employed. The four c l a s s e s of compounds are: « 1) L - a s p a r t i c a c i d amides, L-Asp-NHC H(R )C H ( R ) R Ί

?

1

N=66

2

2

(VII)

1 2 2) L - a s p a r t y l a m i n o e t h y l e s t e r s , L-Asp-NHC H(R )C H(R )OCOR !

1

N=61

2

2

(VIII) 1

2 l

3) L-aspartylaminopropionates, L-Asp-NHC H(R )C H(R )COOR 1

N=31

2

2

(IX)

4) L-aspartylaminoacetates, L-Asp-NHC"^ ( R ^ C O C ^ N=59

(X)

Ν i s the number of compounds i n each c l a s s . QSARs were generated f o r each of the four data bases. A r e p r e s e n t a t i v e multi-dimensional l i n e a r r e g r e s s i o n equation i s that developed f o r the L - a s p a r t y l a m i n o e t h y l e s t e r s (see F i g u r e 2 ) : 2

log(SP)=0.67o*(±0.48)+3.36L (±1.03)-0.29L (±0.08) 2

2

2

+4.18W (±0.88)-0.85W (±0.18)1

1

0.531^10.18)-11.33 n=51

(1) r=0.88

In equation (1) the L^ parameter (9) expresses the length of s u b s t i t u e n t R. to the r e s t of the molecule. W. i s the width upward of R^ when one views i t from the connecting end along the bond a x i s d e f i n i n g L.. The e l e c t r o n i c parameter, σ*, was estimated f o r the s t r u c t u r e s u b s t i t u t e d on the common a s p a r t y l amino moeity, so that the e l e c t r o n i c e f f e c t i s d i r e c t e d to the peptide bond. Ten compounds of the o r i g i n a l 61 do not f i t equation (1); hence n=51, not 61. The a n a l y s i s , i n composite over the four c l a s s e s of L - a s p a r t y l d i p e p t i d e s suggests that the electron-withdrawing e f f e c t of s u b s t i t u e n t s d i r e c t e d to the peptide bond, and the s t e r i c dimensions of the molecules, are important i n e l i c i t i n g the sweet t a s t e . The values o f the r e g r e s s i o n c o e f f i c i e n t s of the σ* term i n the QSAR equations f o r L - a s p a r t i c a c i d amides, L - a s p a r t y l a m i n o e t h y l e s t e r s , and L-aspartylaminopropionates a l l


3.



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are approximately 0.7 suggesting these three c l a s s e s of d i p e p t i d e sweeteners i n t e r a c t i n a common manner at the r e c e p t o r . However, the σ* r e g r e s s i o n c o e f f i c i e n t f o r the L-aspartylaminoacetates QSAR i s approximately 1.5. T h i s v a l u e , along with an examination of the optimum s t e r i c parameter values i n the QSARs, suggest to Iwamura, that the L-aspartylaminoacetates can b e t t e r f i t to the receptor than the other three c l a s s e s of compounds. The QSARs developed by Iwamura provide c o n c i s e r e c i p e s f o r designing d i p e p t i d e sweeteners. However, the uniqueness of an LFE-based QSAR i s always an i s s u e . For t h i s case the s i n g u l a r i t y of the QSARs with respect to the s t e r i c parameters L^, L^ and i s suspect. The values of L^ and can be shown to c o r r e l a t e to the l i p o p h i l i c i t y of R^ as measured by l o g Ρ f o r 38 compounds with a c o r r e l a t i o n c o e f f i c i e n t of .943. Also c o r r e l a t e s with log Ρ f o r 40 choices of R^ with a c o r r e l a t i o n c o e f f i c i e n t of .908. O v e r a l l , i t i s p o s s i b l e to express l o g (SP) as; 9

log(SP)=f(σ*, l o g P ( R ) , l o g P ( R ) ) 1

n=36

r=0.87

(2)

2

s=0.24

The p r a c t i c a l advantage of equation (1) over equation (2) i s that r e l i a b l e estimates of l o g Ρ f o r choices of R^ and R are a v a i l a b l e f o r only 36 of the 51 compounds f o r which L^, and L can be measured. Nevertheless, care needs always to be taken i n e s t a b l i s h i n g the extent of c o r r e l a t i o n uniqueness among LFE d e s c r i p t o r s . T h i s i s normally achieved by c o n s t r u c t i n g a c o r r e l a t i o n matrix among a l l d e s c r i p t o r s considered. 2

2

Extension of the Shallenberger AH...Β Sweetener Model Shallenberger and coworkers(52) proposed what i s probably the most c o n s i s t e n t requirement i n sweeteners, namely the A-H...B hydrogen-bond model. An example of t h i s model, as a p p l i e d by Hopfinger and Jabloner,(53) i s shown i n F i g u r e 3 f o r the a r t i f i c i a l sweetener P-4000 (4000X s u c r o s e ) . In t h i s model the A-H group provides a proton donor f o r a weak i n t r a m o l e c u l a r hydrogen bond to an acceptor Β. Β can be any of a wide range of e l e c t r o n e g a t i v e groups. The d i s t a n c e between the proton and Β i s 2.5-4.OA, a range of values l a r g e r than normally a s s o c i a t e d with hydrogen bonds (1.7-1.9Â). The problem with the A - H — Β model i s that many organic compounds, which are not sweet, c o n t a i n such a grouping. Further, many sweeteners c o n t a i n m u l t i p l e A-H and/or Β groups which makes i t ambiguous i n a s s i g n i n g the r e l e v a n t A-H...Β system. For example, the a r t i f i c i a l sweetener aspartame contains three p o s s i b l e A-H s i t e s and s i x p o s s i b l e Β atoms, see F i g u r e 4. Thus, the u t i l i t y of using the A-H...Β model i n a design mode i s l i m i t e d . A hydro phobic s i t e " l o c a t e d " 5-6A from the A-H...Β system has been suggested(54) as an a d d i t i o n a l c o n s t r a i n i n g f e a t u r e necessary f o r sweeteners. Again a wide range of non-sweet organic compounds meet t h i s a d d i t i o n a l requirement.

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COMPUTERS IN FLAVOR A N D F R A G R A N C E RESEARCH

H

O H Η , η ι ι L. H NC°(L)C—NC (D/L)|;OCO *-=-» I

a

2


COOH /

Figure 2. K^ R , 9

2

R

2

+

General s t r u c t u r e o f the L-aspartylaminoethylesters L , and σ* d e f i n e d . 2

"H" Η. (2.5-4.0 Â)

Η \

/

c\

i

""θ—C~H-

λ

3

7

/

0

Figure 3.

P-UOOO with the A-H

F i g u r e U. M u l t i p l e A-H aspartame.

...

Β system d e f i n e d .

( e l l i p s e s ) and Β (squares)

sites in

with


3.

HOPFINGER A N D WALTERS

27


Therefore, the question a r i s e s i f there a r e a d d i t i o n a l p r o p e r t i e s r e l a t e d to the A-H...Β system that might be c h a r a c t e r i s t i c of sweeteners. Hopfinger and Jabloner(53) were s t r u c k by the unusual geometry of many A-H.. Β systems i n sweeteners. The geometry i n F i g u r e 3 i s exemplary. One could e n v i s i o n the formation o f bimodal hydrogen bonding i n v o l v i n g both Η and Β with i n t e r m o l e c u l a r , r e c e p t o r - s i t e acceptors and donors r e s p e c t i v e l y . These workers proceeded to c a r r y out t h e o r e t i c a l confor mational analyses of a s e t of sweeteners, many of which have m u l t i p l e A-H and/or Β s i t e s . The s e t of compounds analyzed a r e reported i n Table I along with the sweet potency r e l a t i v e to sucrose. A f i x e d valence geometry molecular mechanics f o r c e f i e l d was used i n the conformational analyses. The conforma t i o n a l search s t r a t e g y was as f o l l o w s : 1. Generate a l l i n i t i a l conformer s t a t e s having at l e a s t one A-H...Β system i n which the H...B d i s t a n c e i s i n the 2.5-5.OA range. 2. Minimize the energy of each i n i t i a l conformer as a f u n c t i o n of the allowed t o r s i o n a l degrees o f freedom. 3. A f t e r t o t a l energy minimization r e c o r d / c a l c u l a t e the proper t i e s of the A-H...Β hydrogen bond i n c l u d i n g the bond energy. The most i n t e r e s t i n g o b s e r v a t i o n of t h i s a n a l y s i s i s that each compound i n the data base can e x i s t i n a t l e a s t one s t a b l e conformer f o r which the A-H...Β hydrogen bonding energy E(HB) i s i n the range of -1.5 to -2.5 kcal/mole. F u r t h e r , most potent sweeteners have an E(HB) near -2.0 kcal/mole. The set of E(HB) are reported as p a r t o f Table I, and a histogram p l o t of sweet potency versus E(HB) f o r the compounds of Table I i s shown i n F i g u r e 5. Organic compounds not sweet, but c o n t a i n i n g an A-H...Β system, have a range i n E(HB) v a l u e s of -0.6 to -9.0 kcal/mole. Thus, i t i s tempting to p o s t u l a t e that an a d d i t i o n a l necessary, but perhaps not s u f f i c i e n t , c o n d i t i o n f o r sweetness i s that the A-H..,Β system have an E(HB) i n the -1.5 to -2.5 kcal/mole range. One p o s s i b l e i n t e r p r e t a t i o n of A-H...Β e n e r g e t i c s i s that E(HB) s weaker than -1.5 to -2.5 kcal/mole may not be able to s p a t i a l l y o r i e n t the A-H...Β groups p r o p e r l y while E(HB) s stronger than -2.5 kcal/mole may be too great to allow the receptor B...A-H system to compete with the i n t e r m o l e c u l a r behavior. An obvious questions which a r i s e s i s what f a c t o r s a r e r e s p o n s i b l e f o r E(HB)? A general A-H...Β system i s shown i n F i g u r e 6. The energy E(HB) i s p r o p o r t i o n a l as, f

f

E(HB) OC

ε

f(Θ(ΑΗΒ)) d, ΉΒ

(3)

COMPUTERS IN FLAVOR A N D F R A G R A N C E RESEARCH


28

TABLE I R e l a t i v e sweetness, RS, and hydrogen bond energy, E(HB) of an AH.,.Β system i n a s e t of sweeteners. Number 1 2 3 4 5 6 7

Compound

RS

Ε (HB) kcal/mole

P-4000 APM phyllodulcin (D)-tryptophan (D)-6-Cl tryptophan (D)-serine-O-n-C^H (D)-threonine-O H

4000 180 250 35 1600 320 150

-1, 95 -1, 83 -1, 80 -1.66 -1.85 -1. 72 -1. 75

3000 100 0 3000 25 340 225 130 260

-2.13 -1.92 -1.49 -2, 01 -1, 50 -1, 79 -1, 65 -1, 55 -1, 60

H 7

R NHCH(C=0)NH 1

(CH )nC0 H 2

8 9 10 11 12 13 14 15 16

2

CÔCF 1 COCF^ 1 COCH^ 1 COCF^ 2 cyclamate neohesperidin DHC perillartine acesulfam saccharin

.2 CN NO NO^ CN


3.



Ε (HB)

29

kcal/mole

Figure 5· A histogram o f RS vs. E ( H B ) f o r the s e t o f sweeteners reported i n Table I .

Figure 6.

General s t r u c t u r e o f a hydrogen bond.

30

COMPUTERS IN FLAVOR A N D FRAGRANCE

RESEARCH

Q and Q are the p a r t i a l atomic charges on the proton and Β atoms, r e s p e c t i v e l y , d ^ i s the d i s t a n c e between the Η and Β atoms and f(0(AHB)) i s a s c a l i n g f u n c t i o n between 0 and 1 depending upon the bond angle Θ(ΑΗΒ). The f i x e d molecular d i e l e c t r i c i s expressed as ε. Equation (3) i n d i c a t e s that four v a r i a b l e s c o n t r o l E(HB) and that r e a l i z a t i o n of a small range i n values l i k e -1.5 to -2.5 can be due to competitive c o n t r i b u t i o n s over the four v a r i a b l e s . Nevertheless, i t i s q u i t e i n t e r e s t i n g to observe that these four s t r u c t u r a l v a r i a b l e s i n t e r p l a y to e l i c i t a very t i g h t range i n E(HB) f o r the set of sweeteners considered.


fi

Summary and Prospects The pharmaceutical i n d u s t r y has pioneered i n the a p p l i c a t i o n of computer-assisted drug design methods i n product r e s e a r c h . To a s i g n i f i c a n t degree t h i s i s a consequence of the d i r e c t use of computational chemistry i n enhancing the e f f i c i e n c y of the chemical lead o p t i m i z a t i o n process. For the f l a v o r i n d u s t r y to take s i g n i f i c a n t advantage of q u a n t i t a t i v e molecular design, more s t r i n g e n t measures of b i o l o g i c a l responses are necessary. The a r t i f i c i a l sweetener area represents an example i n f l a v o r chemistry where high q u a l i t y measures of sweet potency have made i t p o s s i b l e f o r QSAR techniques to be s u c c e s s f u l l y a p p l i e d . A l t e r n a t e a r t i f i c i a l f l a v o r i n g areas could be w e l l served by f o l l o w i n g the sweetener example. A great amount of methodology i n molecular design i s now a v a i l a b l e f o r a r t i f i c i a l f l a v o r i n g QSAR a p p l i c a t i o n s . Much of the methodology i s formatted i n easy to use software packages. Thus, computer-assisted molecular design can be viewed as a ready to use a n a l y t i c a l t o o l by f l a v o r chemists. The major b a r r i e r to using these t o o l s i s the l a c k of f a m i l i a r i t y and understanding f l a v o r chemists have with the a v a i l a b l e software. Literature Cited 1.

C. Hansch and A. Leo, "Substituent Constants f o r C o r r e l a t i o n A n a l y s i s in Chemistry and B i o l o g y , " W i l e y - I n t e r s c i e n c e s , New York, 1979. 2. R. R. Rekker, "The Hydrophobic Fragmental Constant," Pharmacochemistry L i b r a r y , V o l . 1, E l s e v i e r , New York, 1977. 3. C. Hansch and J . M. C l a y t o n , J. Pharm. Sci. 1973, 6 2 , 1. 4. M. Charton, Chemtech 1974, 502; 1975, 245. 5. C. Hansch, S. H. Unger, and A. B . Forsythe J . Med. Chem.

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A . J. Hopfinger J. Med. Chem. 1981, 2 4 , 818. A . J. Hopfinger and R. Potenzone, Jr. M o l . Pharmacol. 1982, 21, 187. A . J. Hopfinger J. Med. Chem. 1983, 26, 990. A . S t r e i t w e i s e r , "Molecular O r b i t a l Theory f o r Organic Chemists," W i l e y , New Y o r k , 1961. R. Hoffman J. Chem. Phys. 1963, 39, 1397. J. A . P o p l e , D. P . S a n t r y , and G. A . Segal J. Chem. Phys. 1965, 43, 5129. O. K i k u c h i Bull. Chem. Soc. Japan 1977, 50, 593. R. C. Bingham, M. J. S. Dewar, and D. H . Lo J. Am. Chem. Soc. 1975, 97, 1302. J. L . C o u b e i l s , P h . C o u r r i e r e , and B. Pullman C. R. Acad. Sci., P a r i s 1971, 272, 1813. P . J. Goodford in "Advances i n Pharmacology and Chemotherapeutics," Academic P r e s s , New Y o r k , 1973, p . 52. J. G. T o p l i s s and R. J. C o s t e l l o J. Med. Chem. 1972, 15, 1066. Β. R. Kowalski and C. F . Bender J. Am. Chem. Soc. 1973, 95., 586. R. J. Matthews J. Am. Chem. Soc. 1975, 97, 935. C. L . Perrin Science 1973, 183, 551. L . Bottman Psychometrika 1968, 33, 469. S. S. Schiffman Science 1974, 185, 112. H . Iwamura J. Med. Chem. 1981, 24, 572. R. S. Shallenberger and T. C. Acree Nature (London) 1967, 216, 480. A . J. Hopfinger and H. J a b l o n e r in "The Q u a l i t y of Foods and Beverages," G. Charalambous and G. Inglett, E d s . , Academic P r e s s , New Y o r k , 1981, p . 83. L . B . K i e r J. Pharm. Sci. 1972, 61, 1394.

RECEIVED May

4,

1984

Computer-Based Molecular Design of Artificial Flavoring Agents - ACS

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