Cytotoxic activity and molecular modeling of progestins - pregna-D'-pentarans

Scherbakov, Alexander M.; Левина, И. С.; Куликова, Л. Е.; Fedyushkina, I. V.; Skvortsov, V. S.; Veselovsky, A. V.; Kuznetsov, Yu. V.; Заварзин, И. В.

doi:10.18097/pbmc20166203290

Cited by 5 publications

(3 citation statements)

References 19 publications

(16 reference statements)

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“…So, both genomic and non-genomic effects of progesterone can mediate the cytotoxicity [ 37 ] ( Figure 1 A). In another study, progesterone derivatives pregna-D’-pentaranes inhibited the proliferation of both PR-negative MDA-MB-453 cells and PR-positive MCF-7 cells, but the inhibitory effect was stronger in PR-positive MCF-7 cells [ 44 ].…”

Section: Gestagens As Cytotoxic Drugs Possible Mechanisms and Targetsmentioning

confidence: 99%

Progestins as Anticancer Drugs and Chemosensitizers, New Targets and Applications

Федотчева

Shimanovsky

2021

Pharmaceutics

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Progesterone and its synthetic analogues, progestins, participate in the regulation of cell differentiation, proliferation and cell cycle progression. Progestins are usually applied for contraception, maintenance of pregnancy, and hormone replacement therapy. Recently, their effectiveness in the treatment of hormone-sensitive tumors was revealed. According to current data, the anticancer activity of progestins is mainly mediated by their cytotoxic and chemosensitizing influence on different cancer cells. In connection with the detection of previously unknown targets of the progestin action, which include the membrane-associated progesterone receptor (PR), non-specific transporters related to the multidrug resistance (MDR) and mitochondrial permeability transition pore (MPTP), and checkpoints of different signaling pathways, new aspects of their application have emerged. It is likely that the favorable influence of progestins is predominantly associated with the modulation of expression and activity of MDR-related proteins,the inhibition of survival signaling pathways, especially TGF-β and Wnt/β-catenin pathways, which activate the proliferation and promote MDR in cancer cells, and the facilitation of mitochondrial-dependent apoptosis. Biological effects of progestins are mediated by the inhibition of these signaling pathways, as well as the direct interaction with the nucleotide-binding domain of ABC-transporters and mitochondrial adenylate translocase as an MPTP component. In these ways, progestins can restore the proliferative balance, the ability for apoptosis, and chemosensitivity to drugs, which is especially important for hormone-dependent tumors associated with estrogen stress, epithelial-to-mesenchymal transition, and drug resistance.

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Section: Gestagens As Cytotoxic Drugs Possible Mechanisms and Targetsmentioning

confidence: 99%

Progestins as Anticancer Drugs and Chemosensitizers, New Targets and Applications

Федотчева

Shimanovsky

2021

Pharmaceutics

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“…Как и в предыдущей работе [6], создание предсказательных моделей проводили на основании параметров комплексов, рассчитанных методом MM-PBSA (MM-GBSA) [7]. Подготовку данных, докинг и молекулярную динамику выполняли средствами программ Dock 6.7 [8] и Amber 16.0 [9] (поля сил FF14SB и GAFF2) по схеме, описанной ранее [10]. Время симуляции для молекулярной динамики было по 0,5 нс для каждого из подготовительных этапов (разогрев системы с использованием полноатомной модели воды и кубических периодически граничных условиях, выравнивание давления и уравновешивание системы).…”

Section: методикаunclassified

Creation of a generalized model prediction of inhibition of neuraminidase of influenza virus of various strains

Mikurova

Skvortsov

2018

BIOMED KHIM

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Preliminary results of construction of overall model for prediction of IC50 value of ligands of influenza virus neuraminidase of any strain are presented. We used MM-PBSA (MM-GBSA) energy terms calculated for the complexes obtained after modeling of 30 variants of neuraminidase structures, subsequent docking and simulation of molecular dynamics as independent variables in prediction equations. The structures of known neuraminidase-inhibiting drugs (oseltamivir, zanamivir and peramivir) and a neuraminidase substrate (MUNANA) were used as ligands. The correlation equation based on calculated energetic parameters of inhibitor complexes with neuraminidase did not result in the prediction of IC50 with acceptable parameters (R2£0.3). However, if information about binding energy of the substrate used for neuraminidase assay (and IC50 detection) is included the resulting IC50 prediction equations become significant (R2³0.55). It is concluded that models based on IC50 values as a predictable variable and combining information about binding of different ligands to different variants of the target proteins must take into account the binding properties of the substrate (used for IC50 determination). The predictive power of such models depends critically on the quality of the modeling of the ligand-protein complexes.

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“…Подготовку данных, докинг и молекулярная динамики средствами программ Dock 6.5 [11] и Amber 9.0 [12] (поля сил AMBER99 и GAFF) выполняли по схеме, описанной ранее [13]. Вкратце: до трёх вариантов виртуальных комплексов, отобранных по оценочной функции программы Dock, оптимизировали средствами программы Amber 9.0; далее проводили несколько этапов молекулярной динамики в полноценном водном окружении, последняя (самая длительная) из которых была использована для расчётов изменений свободной энергии комплексов методом MM-PBSA (MM-GBSA) [14].…”

Section: методикаunclassified

Prediction of selective inhibition of neuraminidase from various influenza virus strains by potential inhibitors

2016

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A universal model of inhibition of neuraminidases from various influenza virus strains by a particular has been developed. It is based on known 3D data for neuraminidases from three influenza virus strains (A/Tokyo/3/67, A/tern/Australia/G70C/75, B/Lee/40) and modeling of 3D structure of neuraminidases from other strains (A/PR/8/34 and A/Aichi/2/68). Using docking and molecular dynamics, we have modeled 235 enzyme-ligand complexes for 185 compounds with known IC50 values. Selection of final variants among three results obtained for each enzyme-ligand pair and calculation of independent variables for generation of linear regression equations was performed using MM-PBSA/MM-GBSA. This resulted in the set of equations individual strains and the equations pooling all the data. Thus using this approach it is possible to predict inhibition for neuraminidase from each of the considered strains by a particular inhibitor and to predict the range of its action on neuraminidases from various influenza virus strains.

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Cytotoxic activity and molecular modeling of progestins - pregna-D'-pentarans

Cited by 5 publications

References 19 publications

Progestins as Anticancer Drugs and Chemosensitizers, New Targets and Applications

Progestins as Anticancer Drugs and Chemosensitizers, New Targets and Applications

Creation of a generalized model prediction of inhibition of neuraminidase of influenza virus of various strains

Prediction of selective inhibition of neuraminidase from various influenza virus strains by potential inhibitors

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