Pseudoreceptor Modeling: The Construction of Three-Dimensional Receptor Surrogates

Vedani, Angelo; Zbinden, Peter; Snyder, James P.; Greenidge, Paulette A.

doi:10.1021/ja00122a030

Cited by 84 publications

(51 citation statements)

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“…If we compare this situation to that of mGluR1, we see that both closed (MOL1) and open (MOL2) protomers bind glutamate at active sites lined by the interfaces of subdomains LB1 and LB2 (Kunishima et al, 2000;Tsuchiya et al, 2002) The sweeteners chosen to probe the binding by docking are representative of different families including sugars, peptides and super-sweeteners. Their fit was evaluated semi-quantitatively by means of PrGen (Vedani et al, 1995), a programme that allows the comparison of calculated binding affinity for ligands with the experimental biological activity, i.e. sweetness in our case.…”

Section: Active Sites For Small Sweetenersmentioning

confidence: 99%

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The history of sweet taste: not exactly a piece of cake

Temussi

2006

J of Molecular Recognition

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Understanding the molecular bases of sweet taste is of crucial importance not only in biotechnology but also for its medical implications, since an increasing number of people is affected by food-related diseases like, diabetes, hyperlipemia, caries, that are more or less directly linked to the secondary effects of sugar intake. Despite the interest paid to the field, it is only through the recent identification and functional expression of the receptor for sweet taste that new perspectives have been opened, drastically changing our approach to the development of new sweeteners. We shall give an overview of the field starting from the early days up to discussing the newest developments. After a review of early models of the active site, the mechanisms of interaction of small and macromolecular sweet molecules will be examined in the light of accurate modeling of the sweet taste receptor. The analysis of the homology models of all possible dimers allowed by combinations of the human T1R2 and T1R3 sequences of the sweet receptor and the closed (A) and open (B) conformations of the mGluR1 glutamate receptor shows that only 'type B' sites, either T1R2(B) and T1R3(B), can host the majority of small molecular weight sweeteners. Simultaneous binding to the A and B sites is not possible with two large sweeteners but is possible with a small molecule in site A and a large one in site B. This observation accounted for the first time for the peculiar phenomenon of synergy between some sweeteners. In addition to these two sites, the models showed an external binding site that can host sweet proteins.

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Section: Active Sites For Small Sweetenersmentioning

confidence: 99%

“…Since T1R3 is common to both sweet and (Vedani et al, 1995) as illustrated in . Open circles refer to compounds used in the training set, whereas filled circles refer to compounds of the test set.…”

Section: Active Sites For Small Sweetenersmentioning

confidence: 99%

The history of sweet taste: not exactly a piece of cake

Temussi

2006

J of Molecular Recognition

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“…For pseudoreceptor modeling, the program PrGen 2.1 [29] (SIAT Biographics Laboratory, Basel, CH) was used. Molecules in their lowest-energy conformation were imported in PrGen and reminimized with the Yeti force field.…”

Section: Experimental Section Molecular Modelingmentioning

confidence: 99%

Monatin, Its Stereoisomers and Derivatives: Modeling the Sweet Taste Chemoreception Mechanism

et al. 2005

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The sweet natural compound monatin 1 has two stereogenic centers, and the 2S,4S absolute configuration has been attributed previously to the natural isomer. Among the four stereoisomers of monatin, three of them, particularly the 2R,4R isomer, tastes intensely sweet. The conformations of the four compounds have been studied by means of molecular modelling techniques. Both the diastereoisomeric forms show strong intramolecular hydrogen bonds which involve different functional groups and give rise to two different minimum energy conformations. The tertiary alcohol group in monatin seems to be indirectly involved in the generation of the taste, acting as an important contraint in generating the active conformation. The most important glucophores have

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“…One such approach is the construction of a pseudoreceptor, i.e., a hypothetical model, based upon the structures of some known ligands. The Yak program is perhaps the most well-known computational tool for this purpose [132,133]; other methodologies are also emerging [134,135].…”

Section: Pseudoreceptor Modellingmentioning

confidence: 99%

Evolutionary algorithms in computer-aided molecular design

Clark

Westhead

1996

J Computer-Aided Mol Des

145

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In recent years, search and optimisation algorithms inspired by evolutionary processes have been applied with marked success to a wide variety of problems in diverse fields of study. In this review, we survey the growing application of these 'evolutionary algorithms' in one such area: computer-aided molecular design. In the course of the review, we seek to summarise the work to date and to indicate where evolutionary algorithms have met with success and where they have not fared so well. In addition to this, we also attempt to discern some future trends in both the basic research concerning these algorithms and their application to the elucidation, design and modelling of chemical and biochemical structures.

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Pseudoreceptor Modeling: The Construction of Three-Dimensional Receptor Surrogates

Cited by 84 publications

References 1 publication

The history of sweet taste: not exactly a piece of cake

The history of sweet taste: not exactly a piece of cake

Monatin, Its Stereoisomers and Derivatives: Modeling the Sweet Taste Chemoreception Mechanism

Evolutionary algorithms in computer-aided molecular design

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