In Silico Modeling of Isoniazid-Steroid Conjugates Interactions with Mycobacterial Cytochromes P450 and Their Bioconversion in Vitro by the Cells

Faletrov, Yaroslav V.; Gilep, K A; Falchevskaya, Aleksandra S.; Horetski, M. S.; Panada, J. V.; Andrievskaya, Ekaterina V.; Rudaya, E. V.; Frolova, N. S.; Brzostek, Anna; Plocinska, Renata; Shkumatov, V. M.

doi:10.1134/s1990750821020037

Cited by 3 publications

(4 citation statements)

References 23 publications

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“…Only records about AAs atom coordinates belonging to chain A were used for further processing, but the rest of information was removed. Further formatting was done using standard MGL Tools [15] Python script prepare_receptor4.py resulting in a set of protein les in ready-to-use pdbqt format. Ligand 3D or, if unavailable, 2D structures les were taken from Pubchem (https://pubchem.ncbi.nlm.nih.gov) and BioGem (https://pdt.biogem.org) [16] databases.…”

Section: Dataset Preparationmentioning

confidence: 99%

Application of docking-based inverse high throughput virtual screening to found phytochemical covalent inhibitors of SARS-CoV-2 main protease, NSP12 and NSP16

Faletrov

Staravoitava

Dudko

et al. 2022

Preprint

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Computer-aided docking-based inverse high-throughput virtual screening (inv HTVS) was applied for a quick evaluation of compounds as new affine ligands for SARS-CoV-2 proteins. We performed Autodock Vina-based inv HTVS using more than 450 structures of the virus proteins from Protein Data Bank (PDB) and totally ~ 2000 structures of compound with electrophilic motifs (mainly, α,β-unsaturated carbonyls) from Pubchem (CID codes) or Biogem databases. The inv HTVS calculations were semi-automatically organized, run and analyzed using our helper program tool composed of Python scripts and Excel files with macroses. Criteria for binding energy (Ebind, kcal/mol) values (no more than 6.9), distance between thiol groups of cysteine residues and electrophilic groups of the compounds within 0.4 nm (distance criterium) and total number of structures meeting the criteria were used. New in silico interactions were found for Mpro in the cases of such phytochemicals as peperomine E, 15-oxosteviol, zambesiacolactone B, isodehydroeupatundin, 2deoxycucurbitacin and jatrophone. Analogously, potential covalent ligands for NSP12 were found to include ixerin D, xindongnin C, rabdosin B, epinodosin as well as such ligands for NSP16 were found to include anhydroverlotolin-like compound CID325147, mexicanin E, insulicolide B and geoditin A. These and others hits are discussed with respect to their availability and biological properties. Thus, a set of natural compounds were pointed out as potential new covalent inhibitors of SARS-CoV-2 proteins Mpro, Nsp12 and Nsp16. This information could be used for further evaluations as prophylaxis tools or drugs against COVID-19.

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Section: Dataset Preparationmentioning

confidence: 99%

Application of docking-based inverse high throughput virtual screening to found phytochemical covalent inhibitors of SARS-CoV-2 main protease, NSP12 and NSP16

Faletrov

Staravoitava

Dudko

et al. 2022

Preprint

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“…The intensity of the emission peak of serum albumin decreased regularly and gradually with the gradual increase of the concentration of small molecule substances, indicating that the interaction between small molecule compounds and serum albumin occurred [19][20][21]. Molecular docking can intuitively show the process and results of the interaction between molecules and proteins [22][23][24]. Shang et al determined the binding constant (K A ) and binding site number (n) of hesperidin and glycoside hesperidin with bovine serum albumin (BSA) by fluorescence spectrometry [25].…”

Section: Introductionmentioning

confidence: 99%

A Pilot Study on the Concentration, Distribution and Bioaccumulation of Polybrominated Diphenyl Ethers (PBDEs) in Tissues and Organs of Grassland Sheep

Chen

Yang

Bao

et al. 2022

IJERPH

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Polybrominated diphenyl ether (PBDE) concentrations in various tissues and organs of grassland sheep from Inner Mongolia, China, were determined. The abilities of PBDEs binding to ovine serum albumin (OSA) and Cytochrome P450 enzyme (CYP3A24) were assessed by fluorescence spectroscopy and molecular docking simulations. The PBDE concentrations in the sheep tissue and organ samples were 33.4–167 pg/g dw. The distribution of PBDEs in sheep organs and tissues is affected not only by the function of organs and tissues, but also by the characteristics of PBDEs. Adipose tissue tends to bioaccumulate more-brominated BDEs (BDE-154, -153, and -183), but muscle tissues and visceral organs mainly bioaccumulate less-brominated BDEs. The distribution of PBDEs in visceral organs is mainly affected by the transport of ovine serum albumin (OSA) and the metabolism of CYP3A24 enzyme. The distribution of PBDEs in adipose tissue and brain is mainly affected by their logKOW.

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“…Furthermore, in silico approaches for rational drug design for CYP121 were demonstrated in several earlier studies. For instance, isoniazid hydrazones were assessed as potential mycobacterial CYP121 binders using molecular docking, and their cell penetration was also experimentally validated [ 23 ]. Computational methods are complemented with the experimental pipeline to examine the molecular interactions of inhibitory compounds with CYP121.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the critical residues, i.e., V83, F168, W182, D185, V228, and Q385, for the inhibition of CYP121 by the azole compounds were also elucidated [ 25 ]. Furthermore, ketoconazole was also analyzed for the binding and probable inhibitory potential against most of the Mycobacterium P450 enzymes [ 23 ]. With regard to azole derivatives, the anti-mycobacterium activity of 4-amino-5-(4-fluoro-3-phenoxy phenyl)-4H-1,2,4-triazole-3-thiol (1) and its Schiff bases was also experimentally tested and showed a considerable MIC value (5.5 g/mL) against a multi-drug-resistant (MDR) strain.…”

Section: Introductionmentioning

confidence: 99%

Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of Mycobacterium tuberculosis

et al. 2022

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Due to the concerning rise in the number of multiple- and prolonged-drug-resistant (MDR and XDR) Mycobacterium tuberculosis (Mtb) strains, unprecedented demand has been created to design and develop novel therapeutic drugs with higher efficacy and safety. In this study, with a focused view on implementing an in silico drug design pipeline, a diverse set of glycosylated flavonoids were screened against the Mtb cytochrome-P450 enzyme 121 (CYP121), which is established as an approved drug target for the treatment of Mtb infection. A total of 148 glycosylated flavonoids were screened using structure-based virtual screening against the crystallized ligand, i.e., the L44 inhibitor, binding pocket in the Mtb CYP121 protein. Following this, only the top six compounds with the highest binding scores (kcal/mol) were considered for further intermolecular interaction and dynamic stability using 100 ns classical molecular dynamics simulation. These results suggested a considerable number of hydrogen and hydrophobic interactions and thermodynamic stability in comparison to the reference complex, i.e., the CYP121-L44 inhibitor. Furthermore, binding free energy via the MMGBSA method conducted on the last 10 ns interval of MD simulation trajectories revealed the substantial affinity of glycosylated compounds with Mtb CYP121 protein against reference complex. Notably, both the docked poses and residual energy decomposition via the MMGBSA method demonstrated the essential role of active residues in the interactions with glycosylated compounds by comparison with the reference complex. Collectively, this study demonstrates the viability of these screened glycosylated flavonoids as potential inhibitors of Mtb CYP121 for further experimental validation to develop a therapy for the treatment of drug-resistant Mtb strains.

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In Silico Modeling of Isoniazid-Steroid Conjugates Interactions with Mycobacterial Cytochromes P450 and Their Bioconversion in Vitro by the Cells

Cited by 3 publications

References 23 publications

Application of docking-based inverse high throughput virtual screening to found phytochemical covalent inhibitors of SARS-CoV-2 main protease, NSP12 and NSP16

Application of docking-based inverse high throughput virtual screening to found phytochemical covalent inhibitors of SARS-CoV-2 main protease, NSP12 and NSP16

A Pilot Study on the Concentration, Distribution and Bioaccumulation of Polybrominated Diphenyl Ethers (PBDEs) in Tissues and Organs of Grassland Sheep

Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of Mycobacterium tuberculosis

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