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Pyrazole, imidazole and triazole: In silico, docking and ADMET studies against SARS-CoV-2.

ABSTRACT: The Coronavirus pandemic, Covid-19 and SARS-Cov-2 put multidisciplinary research by chemists, biologists, pharmacists and theorists necessary and primordial task to find new active biomolecules which will be beneficial for all humanity. The azoles drugs are electronic rich, they should be used with caution, and an understanding of their pharmacokinetic profile, safety, absorption, distribution, excretion, metabolism, toxicity, and drug-drug interaction profiles is important to provide effective and cure therapy. In these objectives and goals, twenty aromatic nitrogen heterocycle compounds were chosen for in silico, docking and AMET studies against SARS-CoV-2. In this paper with respect to the protein S of SARS-CoV-2 properties, the GAUSSIAN 09w program used in the semi-empirical method at the AM1 level with the optimization of the geometry of the structures. Then Toxicity and physicochemical properties were evaluated by AMET. Molecular docking investigations conducted; the binding affinities as well as interactions of the sieve compounds with the SRAS-CoV-2 protein Spike using PyRx software. In general, the preliminary results are fructuous and needs further in vitro testes.

SUBMITTER: Mohamed M

PROVIDER: S-EPMC9458701 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Pyrazole, imidazole and triazole: In silico, docking and ADMET studies against SARS-CoV-2.

Mohamed Mounir M Abrigach Farid F El Kadiri Sghir S Omar Said Hassane Said S Abdellattif Magda H MH Touzani Rachid R

Materials today. Proceedings 20220909

The Coronavirus pandemic, Covid-19 and SARS-Cov-2 put multidisciplinary research by chemists, biologists, pharmacists and theorists necessary and primordial task to find new active biomolecules which will be beneficial for all humanity. The azoles drugs are electronic rich, they should be used with caution, and an understanding of their pharmacokinetic profile, safety, absorption, distribution, excretion, metabolism, toxicity, and drug-drug interaction profiles is important to provide effective ...[more]

PMID: 36101672

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Project description:The SARS-Cov-2 virus, which is evolving continuously and causing adverse effects throughout the world, needs an effective drug molecule for its treatment. There are several receptors of SARS Cov-2 which are targeted for its inhibition by many lead molecules both in-vitro and in-vivo. Papain like Protease (PLpro) is one of the two SARS-Cov-2 proteases that can be used as a drug target for SARS Cov-2. It is a coronavirus enzyme that plays a role in the cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex and disruption of host responses. PLpro has also been linked to the cleavage of proteinaceous post translational modifications on host proteins as a means of evading antiviral immune responses. Structure-based drug discovery can be one of the effective methods to screen for various molecules against the target receptors. In this study, PLpro of SARS CoV-2 was chosen as the target for docking. Forty phytochemicals from various plant sources and four synthetic drugs have been screened for their inhibitory potential against PLpro using AutoDock Vina. Phytochemicals such as Tinosponone, Rhoifolin, Rosmanol, Berberin, Nimbin and two other existing drugs Elbasvir and Declatasvir showed higher inhibitory potential in terms of higher binding affinities. ADME and toxicity analysis were also performed to predict the pharmacokinetics and drug likeliness properties. It was concluded from the study that Tinosponone possesss potential inhibitor property of papain-like proteases (PLpro) of SARS CoV-2. Tinosponone from the plant Tinospora cordifolia had a binding affinity of - 9.3 kcal/mol and obeyed the Lipinski rules, making it an effective lead molecule for treating SARS CoV-2. Molecular Dynamics simulation of Tinosponone with PLpro has proved the stability and validity of the binding with RMSD value in range of 0.2 nm when it was run for 50 ns using GROMACS. Therefore, Tinosponone could be considered as a potential inhibitor of PLpro of SARS CoV-2.

Project description:COVID-19 disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) has struck the whole world and raised severe health, economic, and social problems. Many scientists struggled to find a vaccine or an antiviral drug. Eventually, both vaccines and recommended drugs, repurposed drugs, or drug combinations were found, but new strains of SARS-CoV-2 continue to threaten human life and health. As part of the fight against COVID-19 disease, this study involves an in silico molecular docking analysis on the main protease (Mpro) of SARS-CoV-2. To this aim, a Schiff base compound was synthesized and characterized using spectroscopic techniques, including X-ray, FTIR, and UV-Vis. Surface analysis and electronic properties of this molecule were investigated using the DFT method. The drug-likeness parameters of the title compound were studied according to the rules of Lipinski, Veber, Ghose, Egan, and Muegge and were found in agreement with these rules. In silico toxicity analyses revealed that the new compound is a potentially mutagenic and carcinogenic chemical. The title compound was predicted to be an inhibitor of cytochrome P450 enzymes (5 CYPs). This inhibitory effect indicates a weak metabolism of the molecule in the liver. In addition, this compound was displayed good intestinal absorption and blood-brain barrier penetration. The druggability properties of the title compound were investigated, and SwissTargetPrediction predicted it to be a protease inhibitor. In this context, the SARS-CoV-2 main protease was selected as a biological target in molecular docking studies. Docking results were compared with the known native ligand N3 inhibitor. The value of binding energy between the Schiff base compound and the binding pocket of the main protease is higher than that of the reference ligand N3. The calculated free energies of binding of the Schiff base compound and the reference ligand N3 are -8.10 and -7.11 kcal/mol, respectively.

Project description:Background The unique anthropological coronavirus which has been titled as SARS-CoV-2 was originally arisen in late 2019 in Wuhan, China affecting respiratory infection named as COVID-19. Coronavirus is disturbing human life in an exceptional method and has converted a public health global crisis. Natural products are ahead consideration due to the huge beneficial window and effective anti-inflammatory, immunomodulatory, antioxidant and antiviral possessions. Consequently, the present study was intended to display inhibition ability of natural products coumarins and their analogues against SARS coronavirus. Methods The present study, aims to forecast theoretical assembly for the protease of COVID-19 and to discover advance whether this protein may assist as a target for protease inhibitors such as psoralen, bergapten, imperatorin, heraclenin, heraclenol, saxalin, oxepeucedanin, angelicin, toddacoumaquinone, and aesculetin. The docking score of these natural coumarin analogues compared with standard Hydroxychloroquine. Whereas the 3D assembly of main protease of SARS coronavirus was forecast with SWISS MODEL web server, and molecular interaction studies amongst target protein and ligands were done with AutoDock Vina software. Results The study more exposed that all the inhibitors acquired with negative dock energy against the target protein. Molecular docking investigation displayed that natural coumarin analogue toddacoumaquinone displayed a remarkable inhibition ability with the binding energy of ?7.8 kcal/mol than other compounds against main protease of SARS coronavirus in intricate with ?-ketoamide (PDB ID: 5N5O). The synthetic coumarin analogue (1 m) also displayed the comparable inhibition ability with a binding energy of ?7.1 kcal/mol against main protease of SARS coronavirus in intricate with ?-ketoamide. Keeping the overhead results of ADME and toxicity, all tested compounds were recognized as drug-like nature, passing Lipinski’s “Rule of 5” with 0 violation except ?-ketoamide passes Lipinski’s “Rule of 5” with 1 violation MW > 500. The projected constraints are within the assortment of recognized values. Conclusions Based upon the results of the manifold sequence alliance, natural and synthetic coumarin binding sites were preserved. The present in silico examination thus, delivers structural awareness about the protease of COVID-19 and molecular relations with some of the recognised protease inhibitors.

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Pyrazole, imidazole and triazole: In silico, docking and ADMET studies against SARS-CoV-2.

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Pyrazole, imidazole and triazole: In silico, docking and ADMET studies against SARS-CoV-2.

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