Tag Archives: molecular docking

In silico identification and biochemical validation of plausible molecular targets of 4-thiazolidinone derivative Les-3833 as a potential anticancer agent

L. Kоbylinska1*, D. Khylyuk2, I. Subtelna2,
M. Kitsera3, R. Lesyk2

1Department of Biochemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine;
2Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine;
3Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, Ukraine;
*e-mail: Kobylinska_Lesya@meduniv.lviv.ua; lesya8@gmail.com

Received: 16 January 2021; Accepted: 23 April 2021

Synthetic 4-thiazolidinone derivatives have a broad range of pharmacologic activities. Thus, 4-thiazolidinones are being investigated to create new molecules and develop active pharmaceutical substances for anticancer treatment. In our previous study, we investigated the pyrazoline-thiazolidinone-isatin conjugates, and determined that Les-3833 was the most active compound and might act through inhibition of PARP-, MAPK-, JNK-, Bcl-2-, CDK1/cyclin B, and/or the caspase family. The aim of this research was to perform molecular docking studies to enable the construction of a pharmacophore model for the Les-3833 compound and investigate probable biological targets. Pharmacophore modeling software packages performed molecular docking studies of probable biological targets and enabled the construction of a pharmacophore model. Docking models of Les-3833 with 11 enzymes involved in apoptotic mechanisms were studied. Based on the pharmacophore modeling results for all 11 enzymes, Les-3833 is predicted to be most active in Chk‑1, caspase-6, and caspase-8. Immunoblot analysis proved that the application of Les-3833 led to inhibition of Ser345 phosphorylation, which is induced by etoposide, the most important modification responsible for Chk‑1 activity. Taken together with the results of the docking studies, several mechanisms for the expression of antitumor activity by 4-thiazolidinones are suggested, and such multi-affinity is a characteristic feature of all these derivatives. The docking analysis confirmed the affinity of test compound Les-3833 for a topoisomerase II inhibitor and a high possibility of inhibitory interaction with Chk-1, caspase-6, and caspase-8.

Development of effective anti-inflammatory drug candidates among novel thiazolopyridines

T. I. Chaban1*, V. S. Matiychuk2, V. V. Ogurtsov1, I. G. Chaban1, I. A. Nektegayev1

1Danylo Halytsky Lviv National Medical University, Ukraine;
2Ivan Franko National University of Lviv, Lviv, Ukraine;
*e-mail: chabantaras@ukr.net

Received: 26 December 2019; Accepted: 27 March 2020

In an effort to develop novel anti-inflammatory agents, a series of thiazolo[4,5-b]pyridines were synthesized and modified at the N3 position. The structures of the obtained compounds were confirmed by 1H NMR spectroscopy and elemental analysis. The synthesized substances were preselected via molecular docking­ to be tested for their anti-inflammatory activity in vitro. Evaluation of compounds using the carrageenan-induced rat paw edema method showed strong anti-inflammatory action of some compounds (1, 2, 8) which exceeded that of ibuprofen.

New anti-candida active nitrogen-containing bisphosphonates as inhibitors of farnesyl pyrophosphate synthase Candida albicans

L. O. Metelytsia, D. M. Hodyna, O. L. Kobzar,
V. V. Kovalishyn, I. V. Semenyuta

V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry,
National Academy of Sciences of Ukraine, Kyiv;
e-mail: ivan@bpci.kiev.ua

Received: 05 February 2019; Accepted: 14 March 2019

In our previous work, a number of new nitrogen-containing bisphosphonates (N-BPs) with high predicted and experimental antifungal activity were presented as potential Candida albicans farnesyl pyrophos­phate synthase (FPPS) inhibitors. To confirm this hypothesis, a homologous C. albicans FPPS model with high-quality scores has been developed and used in present work to study the molecular mechanism of nit­rogen-containing bisphosphonates action as anti-Candida agents. The known FPPS inhibitors ammonium 2-(Pyridin-2-ylamino)ethylidene-1,1-bisphosphonate, risedronate and alendronate were used in molecular docking analysis. The molecular docking analysis of the new N-BPs demonstrated a number of common features of all ligand’s interaction in the active center of FPPS C. albicans. It is established that the ligands phosphonate groups are the key elements in the formation of the stable ligand-protein complexes with binding energy in a range (ΔG) from –6.6 to –7.1 kcal/mol due to a significant number of electrostatic, hydrogen and metal-acceptor bonds. It is confirmed that the new studied N-BPs 1 and 3 with high anti-Candida activity are FPPS inhibitors.

Designing, docking and heterologous expression of an anti-HER2 affibody molecule

N. Salmanian Tabasi1, A. Gholizadeh1, B. Baghban Kohnehrouz2

1Research Institute for Fundamental Sciences, University of Tabriz, Iran;
2Department of Plant Breeding and Biotechnology, University of Tabriz, Iran;
e-mail: aghz_bioch@yahoo.co.in

Affibody molecules are small protein scaffolds mostly based on triple-helical bundle protein domains. Many triple helix-based affibody proteins have shown prominent properties for tumor imaging and therapy. In our opinion, the structural organizations and the sizes of affibody molecules could be modified to increase their recognition abilities and binding affinities to human epidermal growth factor receptor type 2 (HER2). Thereby, the purpose of this study was to design and characterize a novel platform of affibody molecule consisting of five separate helixes (encoding 99 amino acids with a duplicate of helixes 1 and 2 at N-terminus plus GGGC chelator peptide sequence at C-terminus) enable of binding to HER2 with higher avidity. Using in silico screening methods, the structure and the interactive potential of designed affibody was comparatively investigated. The molecular expression and production of the designed affibody in Escherichia coli cells was successfully examined and reported.


Design of transcription inhibitors on the basis of N-arylamides of 9-methyl- and 9-methoxyphenazine-1-carboxylic acids

L. G. Palchykovska, О. V. Vasylchenko, M. O. Platonov, V. G. Kostina,
N. A. Lysenko, I. V. Alexeeva, D. M. Hovorun, A. D. Shved

Institute of Molecular Biology and Genetics, National Academy
of Sciences of Ukraine, Kyiv,
e-mail: L.Palchykovska@imbg.org.ua

A convenient method of synthesis was develo­ped and two series of N-arylamides of 9-methyl- and 9-methoxyphenazine-1-carboxylic acids were obtained. By the molecular docking method the mode оf the synthesized compounds interaction with catalytic pocket of the RNA polymerase Т7 transcription complex was simulated. Key ligand-receptor intermolecular contacts were identified. They are realized by various types of non-covalent interactions with line of conservative amino acid residues involved in recognition of incoming nucleotide, catalytic act of RNA synthesis as well as in stabilizing the RNA–DNA hybrid at early steps of transcription. In silico data indicate sufficient affinity of ligands for the receptor and allow to predict their ability to inhibit the functioning­ of RNA poly­merase T7 transcription complex that is consistent with preliminary experimental results. Initial testing in a model RNA polymerase T7 transcription system demonstrates significant inhibition of in vitro RNA synthesis by investigated compounds at a concentration of 25 µg/ml (~80 µM).

Effect of fullerene C(60) on ATPase activity and superprecipitation of skeletal muscle actomyosin

K. S. Andreichenko1, S. V. Prylutska1, K. O. Medynska1, K. I. Bogutska1,
N. E. Nurishchenko1, Yu. I. Prylutskyy1, U. Ritter2, P. Scharff2

Joint Ukrainian-German Center on Nanobiotechnology
1Taras Shevchenko National University of Kyiv, Ukraine;
e-mail: prylut@ukr.net;
2Technical University of Ilmenau, Institute of Chemistry
and Biotechnology, Germany

Creation of new biocompatible nanomaterials, which can exhibit the specific biological effects, is an important complex problem that requires the use of last accomplishments of biotechnology. The effect of pristine water-soluble fullerene C60 on ATPase activity and superprecipitation reaction of rabbit skeletal muscle natural actomyosin has been revealed, namely an increase of actomyosin superprecipitation and Мg2+, Са2+– and K+-ATPase activity by fullerene was investigated. We conclude that this finding offers a real possibility for the regulation of contraction-relaxation of skeletal muscle with fullerene C60.