Possibilities of in silico estimations for the development of pharmaceutical composition phytoladaptogene cytotoxic for bladder cancer cells

Ionov N.S.1 , Baryshnikova M.A.2, Bocharov E.V.2, Pogodin P.V.1, Lagunin A.A.1, Filimonov D.A.1, Karpova R.V.2, Kosorukov V.S.2, Stilidi I.S.2, Matveev V.B.2, Bocharova O.A.2, Poroikov V.V.1

1. Institute of Biomedical Chemistry, Moscow, Russia
2. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, Moscow, Russia
Section: Experimental Study
DOI: 10.18097/PBMC20216703278      PubMed Id: 34142535
Year: 2021  Volume: 67  Issue: 3  Pages: 278-288
Based on the prediction of biological activity spectra for several secondary metabolites of medicinal plants using the PASS computer program and validation in vitro of the predictions results the priority direction of the pharmaceutical composition Phytoladaptogene (PLA) development was determined. PLA is a complex of structurally diverse small organic compounds including biologically active substances of phytoadaptogenes (ginsenosides from Panax ginseng, rhodionin from Rhodiola rosea and others) compiled considering previously developed pharmaceutical compositions. Two variants of the pharmaceutical composition were studied: — the major and minor variants included 22 and 13 compounds, respectively. The probability of activity exceeds the probability of inactivity for 1400 out of 1945 pharmacological effects and mechanisms predicted by PASS for the major variant of PLA. The wide range of predicted activities is mainly due to the low structural similarity of constituent compounds. An in silico prediction indicates the possibilities of antitumor properties against bladder, stomach, colon, ovarian and cervical cancers both for minor and major PLA compositions. It was found that the highest probability values of activity were predicted for three mechanisms: apoptosis agonist, caspase-3 stimulant, and transcription factor NF-κB inhibitor. According to the PharmaExpert program they are associated with the antitumor effect against bladder cancer. Experimental validation was using the human bladder cancer cell line RT-112. The results of the MTT test have shown that the cytotoxicity of the major PLA variant is higher than that of the minor PLA variant. In vitro experiments performed using two methods (double staining with annexin V and propidium iodide and detection of active caspase-3 in cells) confirmed that the death of bladder cancer cells occurred via the apoptotic mechanism. The data obtained correspond to the results of the prediction and indicate advantages of the major PLA composition. Thus, PLA can become the basis for the development of a drug with the antitumor activity against bladder cancer. The antitumor activity predicted by PASS for other cancers may be the subject of further studies.
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Keywords: natural products, phytoadaptogenes, in silico estimation, PASS, PharmaExpert, in vitro validation

Ionov, N. S., Baryshnikova, M. A., Bocharov, E. V., Pogodin, P. V., Lagunin, A. A., Filimonov, D. A., Karpova, R. V., Kosorukov, V. S., Stilidi, I. S., Matveev, V. B., Bocharova, O. A., Poroikov, V. V. (2021). Possibilities of in silico estimations for the development of pharmaceutical composition phytoladaptogene cytotoxic for bladder cancer cells. Biomeditsinskaya Khimiya, 67(3), 278-288.
This paper is also available as the English translation: 10.1134/S1990750821040041
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