Tag Archives: molecular docking

Undecylenic acid and N,N-dibutylundecenamide as effective antibacterials against antibiotic-resistant strains

Y. D. Startseva*, D. M. Hodyna, I. V. Semenyuta,
O. P. Tarasyuk, S. P. Rogalsky, L. O. Metelytsia

V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry,
National Academy of Sciences of Ukraine, Kyiv;
*e-mail: startseva1991@gmail.com

Received: 25 April 2023; Revised: 03 July 2023;
Accepted: 7 September 2023; Available on-line: 12 September 2023

Evaluation of undecylenic acid (UA) and its tertiary amide N,N-dibutylundecenamide (DBUA) activity­ in vitro against the standard and antibiotic-resistant Escherichia coli and Staphylococcus aureus strains was carried out. The antibacterial potential of the acid and its amide at 2.5 and 5.0 μM concentration both against gram-positive bacteria (S. aureus) and gram-negative (E. coli) cultures was confirmed by monitoring the diameter of the bacterial growth inhibition zones. The docking study identified methionine aminopeptidase (MAP) as the most energy-favorable potential biotarget associated with the drug resistance of E. coli and S. aureus with a binding energy in the range from -8.0 to -8.5 kcal/mol. The ligands complexation was due to the formation of hydrogen bonds with ASP108, HIS171, HIS178, GLU204, GLU235, HIS76, ASP104, GLU233, ASP93 and metal-acceptor interactions with Co2+. Overall, the results indicated that UA and DBUA activity against antibiotic-resistant strains creates prospects for the development of new antibacterial formulations.

Cathepsin inhibitors as potent inhibitors against SARS-CoV-2 main protease. In silico molecular screening and toxicity prediction

O. Sekiou1*, W. Kherfane2, M. Boumendjel3,
H. Cheniti4, A. Benselhoub1*, S. Bellucci5

1Environmental Research Center, Annaba, Algeria;
2Laboratory of Geodynamics and Natural Resources, Department of Hydraulics,
Badji Mokhtar Annaba University, Annaba, Algeria;
3Laboratory of Biochemistry and Environmental Toxicology,
Badji Mokhtar Annaba University, Algeria;
4National High School of Technology and Engineering (ESTI), Annaba, Algeria;
5INFN Frascati National Laboratories, Rome, Italy;
*e-mail: aissabenselhoub@cre.dz; sekiouomar@yahoo.fr

Received: 05 March 2023; Revised: 28 March 2023;
Accepted: 13 April 2023; Available on-line: 27 April 2023

Since the emergence of the newly identified Coronavirus SARS-CoV-2, no targeted therapeutic agents for COVID-19 treatment are available, and effective treatment options remain very limited. Successful crystallization of the SARS-CoV-2 main protease (Mpro, PDB-ID 6LU7) made possible the research on finding its potential inhibitors for the prevention of virus replication. To conduct molecular docking, we selected ten representatives of the Cathepsin inhibitors family as possible ligands with a high potential of binding the active site of SARS-CoV-2 main protease as a potential target. The results of molecular docking studies revealed that Ligand1 and Ligand2, with vina scores -8.8 and -8.7 kcal/mol for Mpro, respectively, were the most effective in binding. In silico prediction of physicochemical and toxicological behavior of assessed ligands approved the possibility of their use in clinical essays against SARS-COVID-19.

Prediction of pEC50(M) and molecular docking study for the selective inhibition of arachidonate 5-lipoxygenase

N. R. Das1, P. G. R. Achary2*

1Department of CSIT, Siksha ‘O’ Anusandhan deemed to be University, Bhubaneswar, Odisha, India;
2Department of Chemistry, Faculty of Engineering and Technology (ITER), Siksha ‘O’ Anusandhan deemed to be University, Bhubaneswar, Odisha, India;
*e-mail: pgrachary@soa.ac.in

Received: 28 April 2021; Accepted: 12 November 2021

Arachidonate 5-lipoxygenase (ALOX5) is considered a prime target for drug discovery in the area of liver fibrosis, rheumatoid arthritis, atherosclerosis, cancer and asthma. To date, the lead rate in the discovery of drugs that inhibit ALOX5 for the treatment of the above diseases is not satisfactory. So, the development of powerful and effective ALOX5-targeted drugs is desired. In this regard, Quantitative Structure-Activity Relationship (QSAR) and molecular docking can have a major role in screening and designing drugs. In this work, 3D-QSAR models were proposed, which were built using the techniques like Multiple Linear Regression (MLR), and Partial Least Squares (PLS) for the pEC50(M) taking a diverse dataset of 112 molecules. The technique of the ‘Index of Ideality of Correlation (IIC)’ was also investigated to generate an optimal descriptor derived from the SMILES molecular structure. The effect of the number and nature of descriptors on the model were analyzed. The models can be helpful in providing better directions for the development of novel drug targets for 5-lipoxygenase. A significant improvement in the stability of the model was observed by the incorporation of the optimal descriptor. The molecular docking results showed that the ALOX5 receptor was well inhibited by the 112 ligands showing the least binding energy (-10.8 Kcal/mol).  In order to validate the binding mode of the ligands docked with AutoDock Vina software, the top-scored compounds were re-docked using DockThor online docking server. The results obtained from docking suggest that the ligands with IDs 18, 20, 24, 30 and 44 are some of the potential inhibitors for ALOX5.

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.