Electrostatic Recognition Patterns of Sweet-Tasting Compounds

Chapter 14

Electrostatic Recognition Patterns of Sweet-Tasting Compounds Thomas J. Venanzi and Carol A. Venanzi 1

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Department of Chemistry, College of New Rochelle, New Rochelle, N Y 10805 Department of Chemical Engineering, Chemistry, and Environmental Science, New Jersey Institute of Technology, Newark, N J 07102 1

Downloaded by IOWA STATE UNIV on April 19, 2017 | http://pubs.acs.org Publication Date: December 31, 1991 | doi: 10.1021/bk-1991-0450.ch014

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Molecular electrostatic potential (MEP) patterns are determined for a select set of p e r i l l a r t i n e analogues. The op timal recognition pattern for these compounds i s deduced from the electro s t a t i c potential generated by the most potent 1,4-analogues. Similar patterns are found for the chemically related class of compounds, the 2-substituted 5-nitroanilines. The implications for tastant-receptor binding are discussed.

E l e c t r o n i c i n t e r a c t i o n s p l a y an important r o l e i n the i n t e r a c t i o n between sweet t a s t a n t s and t h e i r r e c e p t o r s ( 1 ) . Some e l e c t r o n i c f e a t u r e s p o s t u l a t e d t o be i n v o l v e d i n the a c t u a l b i n d i n g of sweet t a s t a n t s t o the receptor have been d e r i v e d from a simple model suggested (2,3.) by a c o n s i d e r a t i o n o f a number o f s t r u c t u r a l l y d i v e r s e t a s t a n t s such as f r u c t o s e , s a c c h a r i n , and chloroform. T h i s model suggests t h a t the b i n d i n g takes place between an e l e c t r o n e g a t i v e atom (B) on the t a s t a n t and an e l e c t r o p o s i t i v e hydrogen on the r e c e p t o r , as w e l l as between a p o l a r i z e d system (A-H) on the t a s t a n t and an e l e c t r o n e g a t i v e atom on the receptor. A d i s t a n c e o f 2 . 0 - 3 . O A between A and Β has been p o s t u l a t e d as a requirement t o i n i t i a t e the t a s t e response ( 2 ) . An additional electronic feature of the t a s t a n t , i d e n t i f i e d by a hydrophobic s i t e l o c a t e d on the t a s t a n t at a d i s t a n c e o f 5 . 0 - 6 . 0 Â from B, was assumed i n the model i n order t o r a t i o n a l i z e the t a s t e potency ( 2 ) · I t has been pointed out ( 4 ) t h a t many organic compounds possess such f e a t u r e s and are c l e a r l y not very sweet. In a d d i t i o n , f o r t a s t a n t s such as the p e r i l l a r t i n e analogues and the 2 - s u b s t i t u t e d 5 - n i t r o a n i l i n e s , i t i s

0097-6156/91/0450-0193$06.00A) © 1991 American Chemical Society

Walters et al.; Sweeteners ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

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DISCOVERY, M O L E C U L A R DESIGN, A N D

CHEMORECEPTION

not p o s s i b l e t o determine a p o l a r i z e d A-H moiety t h a t would s a t i s f y the above requirement and a l s o form strong hydrogen bonds with the receptor (4). Furthermore, for the strong acids saccharin and acesulfame, i t has been shown that i t i s the a n i o n i c form which i s the b i o l o g i c a l l y a c t i v e species ( 5 ) . To i n v e s t i g a t e the e l e c t r o n i c requirements f o r sweet-taste a c t i v a t i o n , we have i n i t i a l l y focussed on the f i r s t stage of molecular r e c o g n i t i o n , i . e . , the long range i n t e r a c t i o n of the t a s t a n t with the receptor which o r i e n t s the t a s t a n t i n the r e c e p t o r s a c t i v e s i t e . T h i s p r e l i m i n a r y i n t e r a c t i o n between the receptor and t a s t a n t i s dominated by long-range e l e c t r o s t a t i c interactions, which can be measured by the e l e c t r o s t a t i c p o t e n t i a l p a t t e r n of the t a s t a n t . T h i s p a t t e r n y i e l d s the e l e c t r o s t a t i c p o t e n t i a l energy of i n t e r a c t i o n between a u n i t p o s i t i v e charge l o c a t e d at any p o i n t i n space and the s t a t i c charge d i s t r i b u t i o n of the molecule ( 6 ) . Since the molecular e l e c t r o s t a t i c p o t e n t i a l (MEP) i s a property of the molecule as a whole, i t provides the b a s i s f o r the development of a g l o b a l model of e l e c t r o s t a t i c r e c o g n i t i o n . For a given c l a s s of t a s t a n t s a c t i n g at the same receptor s i t e , we assume that the MEP p a t t e r n of the most potent t a s t a n t s defines the optimal pattern for electrostatic r e c o g n i t i o n by the r e c e p t o r . The optimal molecular e l e c t r o s t a t i c p o t e n t i a l p a t t e r n provides information about (1) the o r i e n t a t i o n of the tastant i n the receptor c a v i t y and (2) the electrostatic pattern a s s o c i a t e d with the receptor. This information is especially crucial in the case of sweet-taste r e c o g n i t i o n where the sweet-taste receptor has not been physically isolated. Though the e l e c t r o s t a t i c energy i s o f t e n the major c o n t r i b u t i o n to the b i n d i n g energy, other terms such as p o l a r i z a t i o n , charge t r a n s f e r , d i s p e r s i o n e t c . may a l s o be important to the b i n d i n g energy ( 7 ) . However, s i n c e the e l e c t r o s t a t i c p o t e n t i a l determines the o r i e n t a t i o n of the t a s t a n t with r e s p e c t to the receptor s i t e , the molecular electrostatic p o t e n t i a l patterns can be u t i l i z e d to form a p r e l i m i n a r y hypothesis concerning the molecular characteristics of tastant-receptor b i n d i n g . Such a program has been used by Weinstein e t a l . ( 8 ) to determine the mechanism f o r the b i n d i n g of 5-HT and i t s congeners and r e l a t e d compounds to the serotonin receptor. Our i n i t i a l work has d e a l t with the s e m i - r i g i d perillartine analogues f o r which structure-activity data are available (9). These analogues are c h a r a c t e r i z e d by a CC double bond i n conjugation with the CN double bond of the oxime moiety. We focussed on a s e l e c t s e t of compounds, c h a r a c t e r i z e d with one exception by their predominantly sweet t a s t e . The compounds of i n t e r e s t are l i s t e d i n Figure 1. Our f i r s t


1


14. VENANZI & VENANZI

195

Electrostatic Recognition Patterns

OH I

Ν

OH CH

" V

1

!


3

OH,

[55x;

40/16]

OH

OH I

Η ^

N

CH,

[40x;

55/8]

8

[225x; 90/2]

[90x;

50/15]

OH

OH

"V'SH, I

CH 3

[200x; 70/3]

[55x;

48/7]

[140x; 0/57]

Figure 1. Chart of compounds. The t a s t e potencies of the p e r i l l a r t i n e analogues are given by X (times sucrose). A l s o given are the r a t i o s of sweetness t o bitterness. Walters et al.; Sweeteners ACS Symposium Series; American Chemical Society: Washington, DC, 1991.


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DISCOVERY, M O L E C U L A R DESIGN, A N D C H E M O R E C E P T I O N

task was t o i d e n t i f y the a c c e s s i b l e conformations f o r these compounds. In order t o do t h i s , we performed a conformational analysis on the simplest compound, (Ε,Ε)-tiglaldoxime, 2 , t o determine the low-energy conformers (10). The t o r s i o n a l angles of i n t e r e s t were the CNOH and CCCN d i h e d r a l angles. The conformational a n a l y s i s was done with the ab i n i t i o 3-21G b a s i s s e t . A s e l e c t s e t of c a l c u l a t i o n s on t i g l a l d o x i m e with the 4-31G and 6-31G* b a s i s s e t s y i e l d e d n e a r l y i d e n t i c a l r e s u l t s t o those employing the 3-21G basis s e t . After i d e n t i f y i n g the low-energy conformers, the molecular e l e c t r o s t a t i c p o t e n t i a l (MEP) p a t t e r n s were c a l c u l a t e d f o r the most potent compounds i n F i g u r e 1 i n order t o d e f i n e the optimal r e c o g n i t i o n p a t t e r n (11). In a d d i t i o n , the MEP p a t t e r n s were a l s o calculated f o r a select s e t o f the l e s s potent compounds i n Figure 1 (11). In the present work, we have a l s o extended the MEP a n a l y s i s t o another s e t of sweet t a s t a n t s , the 2 - s u b s t i t u t e d 5 - n i t r o a n i l i n e s , f o r which s t r u c t u r e - a c t i v i t y data are a v a i l a b l e (12). We s e l e c t e d t h i s s e t of compounds not only f o r t h e i r t o p o l o g i c a l s i m i l a r i t y t o the p e r i l l a r t i n e s , but a l s o because there i s no experimental evidence t o i n d i c a t e t h a t i n lower animals they operate at different r e c e p t o r s (13). The e l e c t r o s t a t i c p o t e n t i a l p a t t e r n s of a s m a l l subset o f these compounds were determined (Venanzi, T.J.; Venanzi, C.A., unpublished data) and are compared here t o the MEP p a t t e r n s generated by the perillartine analogues. A l l the MEP maps were c a l c u l a t e d u s i n g the 3-21G b a s i s s e t . Conformational A n a l y s i s o f Tastants E l e c t r o s t a t i c p o t e n t i a l p a t t e r n s are g e n e r a l l y more dependent on t o r s i o n a l angle changes than on changes i n bond angles and bond l e n g t h s . In the p e r i l l a r t i n e analogues two t o r s i o n a l angles are important, namely, the CNOH and CCCN angles. Since i n t e r a c t i o n with the receptor or solvent can provide energy of stabilization, the b i o l o g i c a l l y a c t i v e (accessible) conformers may, i n f a c t , be a t l e a s t 3-4 kcal/mol higher i n energy than the most s t a b l e conformer i n vacuo (14). We used the ab i n i t i o 3-21G b a s i s s e t t o study the r e l a t i o n s h i p between the CNOH and CCCN angles and the energy o f (Ε,Ε)-tiglaldoxime. The GAUSSIAN-82 package (L5) was used f o r the conformational a n a l y s i s of (Ε,Ε)-tiglaldoxime as w e l l as f o r the c a l c u l a t i o n of the electrostatic potential of the compounds o f interest. The geometry o f (Ε,Ε)-tiglaldoxime was optimized f o r every angle i n the study. For the o p t i m i z a t i o n of the CNOH angle, the CCCN angle was s e t to 180 degrees. For the o p t i m i z a t i o n o f the CCCN angle the CNOH angle was s e t t o 180 degrees. Our r e s u l t s are given i n Table I .


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Electrostatic Recognition Patterns

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Table I . Energy of ( E , E ) - t i g l a l d o x i m e as a f u n c t i o n o f

Electrostatic Recognition Patterns of Sweet-Tasting Compounds

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