Consensus Drug Design Using IT Microcosm

Vassiliev, Pavel; Косолапов, В. А.; Kucheryavenko, A. F.; Гурова, Н. А.; Анисимова, В. А.

doi:10.1007/978-94-017-9257-8_12

Cited by 23 publications

(22 citation statements)

References 42 publications

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“…Table 2 presents the indices of significance of the predicted biotargets, as calculated by a Microcosm BioS system [ 20 , 21 ] and reflecting the magnitude of the impact of the studied bornyl derivatives on these biotargets as well as structural similarity of these compounds to the nearest analogues from the quantitative structure–activity relationship (QSAR) base of standards.…”

Section: Resultsmentioning

confidence: 99%

“…For comprehensive in silico evaluation of the compounds' mechanism of hypoglycemic action, 24 key biotargets (Table 1) were chosen that had been verified in molecular pharmacology as important factors of diabetes pathogenesis [16][17][18]. Table 2 presents the indices of significance of the predicted biotargets, as calculated by a Microcosm BioS system [20,21] and reflecting the magnitude of the impact of the studied bornyl derivatives on these biotargets as well as structural similarity of these compounds to the nearest analogues from the quantitative structure-activity relationship (QSAR) base of standards.…”

Section: In Silico Analysismentioning

confidence: 99%

“…Indices for highly important targets (strongly explaining the hypoglycemic activity) are bold; indices for medium-importance targets are bold and italic; other targets are defined as low-importance targets 2. The average QL-modified Tanimoto similarity coefficient[20,22]. The values corresponding to high similarity of predicted and reference structures are highlighted in bold.Table 3presents a profile of calculated activity levels for each of the four studied substances in relation to 24 analyzed biotargets.…”

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confidence: 99%

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Bornyl Derivatives of p-(Benzyloxy)Phenylpropionic Acid: In Vivo Evaluation of Antidiabetic Activity

et al. 2020

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A series of bornyl derivatives of p-(benzyloxy)phenylpropionic acid were prepared, and their hypoglycemic activities were examined by an oral glucose tolerance test in mice. The results of this test revealed two compounds, 1 and 3, that can reduce the blood level of glucose similarly to reference compound vildagliptin. Both compounds were tested in an experiment on mice with metabolic disorders: the C57BL/6Ay strain. Along with hypoglycemic properties, the two compounds showed different abilities to correct lipid metabolism disorders. In silico prediction revealed that the studied substances are most likely bifunctional multitarget hypoglycemic compounds whose mechanism of action is based on a pronounced reduction in insulin resistance and a strong incretin-mimetic effect. The difference in the size of effects of these compounds on biochemical parameters of blood in the experiment on C57BL/6Ay mice was in good agreement with the computational prediction of the priority ranking of biological targets for these compounds. These results indicate that bornyl derivatives of p-(benzyloxy)phenylpropionic acid have a good potential as new agents for diabetes mellitus treatment due to their hypoglycemic and lipid-normalizing properties.

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Section: Resultsmentioning

confidence: 99%

Section: In Silico Analysismentioning

confidence: 99%

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confidence: 99%

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Bornyl Derivatives of p-(Benzyloxy)Phenylpropionic Acid: In Vivo Evaluation of Antidiabetic Activity

et al. 2020

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“…In order to identify the most promising antidiabetic substances using IT Microcosm [25,26] and PASS computer systems [27,28], a step-by-step detailed in silico analysis of the hypoglycemic properties of the new compounds was carried out. Programs DruLiTo [29] and QikProp [30] were employed to assess key ADME properties and characteristics.…”

Section: Resultsmentioning

confidence: 99%

“…IT Microcosm [25,26] and PASS [27,28] computer systems were employed to determine the most promising chemical class of compounds. A training set of known hypoglycemic drugs and a library of tested benzimidazole derivatives were subjected to a consensus prediction of the level of hypoglycemic activity.…”

Section: In Silico Studymentioning

confidence: 99%

Antidiabetogenic Features of Benzimidazoles

Спасов¹,

Vassiliev²,

Анисимова³

et al. 2019

Chemistry and Applications of Benzimidazole and Its Derivatives

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Literature data on the insulinogenic effect of 2-aminobenzimidazole prompted us to investigate its novel derivatives, particularly those containing an additional fused cycle in C1,2-α position, including imidazole, dihydroimidazole, or tetrahydropyrimidine ring. Consensus analysis of the hypoglycemic effect of these compounds performed with IT Microcosm and PASS system revealed that activity is mostly characteristic for N 9 -2,3-dihydroimidazo[1,2-a]benzimidazole derivatives. Substructural analysis of hypoglycemic activity identified substituents that determine the greatest pharmacological effect. According to the in silico assessment of the ADME properties, RU-254 was nominated as a lead compound due to the most optimal calculated and experimental activity and pharmacokinetic parameters. Preclinical studies have shown that identified compound has a pronounced insulinogenic effect and hypoglycemic effect, both in intact animals and in animals with experimental diabetes mellitus. RU-254 also reduces the level of glycated hemoglobin upon chronic administration, slightly decreases the activity of DPP-4, and increases the average number of Langerhans islets in the pancreas. Pharmaceutical drug formulation of RU-254 was developed and investigated for pharmacokinetic, pharmacodynamic, and toxicological properties. The dosage form of the drug under the name limiglidol (compound RU-254, diabenol) was evaluated in the full cycle of clinical studies that confirmed the safety, tolerability, and prominent antidiabetic properties of the drug.

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Synthesis and Evaluation of Novel [1,2,4]Triazolo[5,1‐c][1,2,4]‐triazines and Pyrazolo[5,1‐c][1,2,4]triazines as Potential Antidiabetic Agents

Русинов

Сапожникова

Bliznik

et al. 2017

Archiv der Pharmazie

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Inhibition of the dipeptidyl peptidase-4 (DPP4) enzyme activity and prevention of advanced glycation end (AGE) products formation represents a reliable approach to achieve control over hyperglycemia and the associated pathogenesis of diabetic vascular complications. In the frames of this research study, several triazolo- and pyrazolotriazines were synthesized and evaluated as inhibitors of AGE products formation, DPP4, glycogen phosphorylase and α-glucosidase activities, as well as AGE cross-link breakers. From the two considered classes of heterocyclic compounds, the pyrazolotriazines showed the highest potency as antiglycating agents and DPP4 inhibitors. Structure-activity relationships (SAR) for these compounds, which can be considered as potential drugs for the treatment of type 2 diabetes, were evaluated.

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Consensus Drug Design Using IT Microcosm

Cited by 23 publications

References 42 publications

Bornyl Derivatives of p-(Benzyloxy)Phenylpropionic Acid: In Vivo Evaluation of Antidiabetic Activity

Bornyl Derivatives of p-(Benzyloxy)Phenylpropionic Acid: In Vivo Evaluation of Antidiabetic Activity

Antidiabetogenic Features of Benzimidazoles

Synthesis and Evaluation of Novel [1,2,4]Triazolo[5,1‐c][1,2,4]‐triazines and Pyrazolo[5,1‐c][1,2,4]triazines as Potential Antidiabetic Agents

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