Self-Organizing Neural Networks for Screening and Development of Novel Artificial Sweetener Candidates

Polański, Jarosław; Gasteiger, Johann; Jarzembek, Krystyna

doi:10.2174/1386207003331427

Cited by 26 publications

(37 citation statements)

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“…[17][18][19] One particular appeal of the method presented here is the fact that both SAR modeling and focused library design can be performed in one step by nonlinear mapping. Traditional SAR models usually aim at identifying individual parameters that have influence on molecular activity.…”

Section: Resultsmentioning

confidence: 99%

Ligand-Based Combinatorial Design of Selective Purinergic Receptor (A_2A) Antagonists Using Self-Organizing Maps

Schneider

Nettekoven

2003

J. Comb. Chem.

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A virtual screening procedure based on a topological pharmacophore similarity metric and self-organizing maps (SOM) was developed and applied to optimizing combinatorial products functioning as P(1) purinergic receptor antagonists. The target was the human A(2A) receptor. A SOM was developed using a set of biologically tested molecules to establish a preliminary structure-activity relationship. A combinatorial library design was performed by projecting virtually assembled new molecules onto the SOM. A small focused library of 17 selected combinatorial products was synthesized and tested. On average, the designed structures yielded a 3-fold smaller binding constant ( approximately 33 vs approximately 100 nM) and 3.5-fold higher selectivity (50 vs 14) than the initial library. The most selective compound obtained revealed a 121-fold relative selectivity for A(2A) with K(i) (A(2A)) = 2.4 nM, and K(i) (A(1)) = 292 nM. This result demonstrates that it was possible to design a small, activity-enriched focused library with an improved property profile using the SOM virtual screening approach. The strategy might be particularly useful in projects in which structure-based design cannot be applied because of a lack of receptor structure information, for example, in the many projects aiming at finding new GPCR modulators.

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Section: Resultsmentioning

confidence: 99%

Ligand-Based Combinatorial Design of Selective Purinergic Receptor (A_2A) Antagonists Using Self-Organizing Maps

Schneider

Nettekoven

2003

J. Comb. Chem.

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“…As a result, 10,000-30,000 points sampled at the surface are mapped to about 400-2500 (20x20 to 50x50) neurons arranged into a two-dimensional map of electrostatic potential or another molecular feature. This technique has been used for the comparison of individual maps of bioactive compounds [12] or bioisosteric moieties [22,23]. Although the robust neuron technique is considered to be an efficient comparison tool, the rules for this comparison are actually very unclear.…”

Section: Feature Maps Of the Molecular Electrostatic Potentialmentioning

confidence: 99%

Comparative Molecular Surface Analysis (CoMSA) for Virtual Combinatorial Library Screening of Styrylquinoline HIV-1 Blocking Agents

Niedbala

Polański²,

Gieleciak³

et al. 2006

CCHTS

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We used comparative molecular surface analysis to design molecules for the synthesis as part of the search for new HIV-1 integrase inhibitors. We analyzed the virtual combinatorial library (VCL) constituted from various moieties of styrylquinoline and styrylquinazoline inhibitors. Since imines can be applied in a strategy of dynamic combinatorial chemistry (DCC), we also tested similar compounds in which the -C=N- or -N=C- linker connected the heteroaromatic and aromatic moieties. We then used principal component analysis (PCA) or self-organizing maps (SOM), namely, the Kohonen neural networks to obtain a clustering plot analyzing the diversity of the VCL formed. Previously synthesized compounds of known activity, used as molecular probes, were projected onto this plot, which provided a set of promising virtual drugs. Moreover, we further modified the above mentioned VCL to include the single bond linker -C-N- or -N-C-. This allowed increasing compound stability but expanded also the diversity between the available molecular probes and virtual targets. The application of the CoMSA with SOM indicated important differences between such compounds and active molecular probes. We synthesized such compounds to verify the computational predictions.

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“…This was used successfully by the Merck group to design and obtain the endothelin antagonist [10,11]. Therefore, we simulated such maps for some molecules related to arylsulfonylalkanoic acids [12]. Tetrazole and amide functions are possible replacements, and, in fact, both can be found in sweeteners.…”

Section: Synthetic Targetsmentioning

confidence: 99%

Search for new sulfonyl-containing glucophores

Polański

Jarzembek

2002

Pure and Applied Chemistry

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A number of sweeteners contain the sulfur atom and a sulfonyl group. In our current search for new glucophores, several new compounds containing a sulfonyl group were obtained. Synthetic targets have been found both by intuitive modifications of the structural motifs of the known sweet compounds and by the use of molecular modeling techniques. We developed the efficient synthetic routes yielding these compounds and obtained a number of these analogs. We have evaluated the taste quality of the amides and sulfonylated amino acids, finding out that almost all of them are bitter actives. We are now performing basic toxicological tests preceding the systematic taste study within the tetrazoles obtained.

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Self-Organizing Neural Networks for Screening and Development of Novel Artificial Sweetener Candidates

Cited by 26 publications

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Ligand-Based Combinatorial Design of Selective Purinergic Receptor (A_2A) Antagonists Using Self-Organizing Maps

Ligand-Based Combinatorial Design of Selective Purinergic Receptor (A_2A) Antagonists Using Self-Organizing Maps

Comparative Molecular Surface Analysis (CoMSA) for Virtual Combinatorial Library Screening of Styrylquinoline HIV-1 Blocking Agents

Search for new sulfonyl-containing glucophores

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Self-Organizing Neural Networks for Screening and Development of Novel Artificial Sweetener Candidates

Cited by 26 publications

References 0 publications

Ligand-Based Combinatorial Design of Selective Purinergic Receptor (A2A) Antagonists Using Self-Organizing Maps

Ligand-Based Combinatorial Design of Selective Purinergic Receptor (A2A) Antagonists Using Self-Organizing Maps

Comparative Molecular Surface Analysis (CoMSA) for Virtual Combinatorial Library Screening of Styrylquinoline HIV-1 Blocking Agents

Search for new sulfonyl-containing glucophores

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Product

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Ligand-Based Combinatorial Design of Selective Purinergic Receptor (A_2A) Antagonists Using Self-Organizing Maps

Ligand-Based Combinatorial Design of Selective Purinergic Receptor (A_2A) Antagonists Using Self-Organizing Maps