Synthesis, DFT and In Silico Anti-COVID Evaluation of Novel Tetrazole Analogues (original) (raw)
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Journal of Biomolecular Structure and Dynamics, 2021
In this work we aimed to perform an in silico predictive screening, docking and molecular dynamic study to identify 1,2,3-triazole-phthalimide derivatives as drug candidates against SARS-CoV-2. The in silico prediction of pharmacokinetic and toxicological properties of hundred one 1,2,3-triazole-phtalimide derivatives, obtained from SciFinderV R library, were investigated. Compounds that did not show good gastrointestinal absorption, violated the Lipinski's rules, proved to be positive for the AMES test, and showed to be hepatotoxic or immunotoxic in our ADMET analysis, were filtered out of our study. The hit compounds were further subjected to molecular docking on SARS-CoV-2 target proteins. The ADMET analysis revealed that 43 derivatives violated the Lipinski's rules and 51 other compounds showed to be positive for the toxicity test. Seven 1,2,3-triazole-phthalimide derivatives (A7, A8, B05, E35, E38, E39, and E40) were selected for molecular docking and MFCC-ab initio analysis. The results of molecular docking pointed the derivative E40 as a promising compound interacting with multiple target proteins of SARS-CoV-2. The complex E40-M pro was found to have minimum binding energy of À10.26 kcal/mol and a general energy balance, calculated by the quantum mechanical analysis, of À8.63 eV. MD simulation and MMGBSA calculations confirmed that the derivatives E38 and E40 have high binding energies of À63.47 ± 3 and À63.31 ± 7 kcal/mol against SARS-CoV-2 main protease. In addition, the derivative E40 exhibited excellent interaction values and inhibitory potential against SAR-Cov-2 main protease and viral nucleocapsid proteins, suggesting this derivative as a potent antiviral for the treatment and/or prophylaxis of COVID-19.
De gruyter, 2021
Objectives: Presently, the pandemic of COVID-19 has worsened the situation worldwide and received global attention. The United States of America have the highest numbers of a patient infected by this disease followed by Brazil, Russia, India and many other countries. Moreover, lots of research is going on to find out effective vaccines or medicine, but still, no potent vaccine or drug is discovered to cure COVID-19. As a consequence, many types of research have designated that computer-based studies, such as protein-ligand interactions, structural dynamics, and chembio modeling are the finest choice due to its low cost and time-saving features. Here, oxindole derivatives have been chosen for docking because of their immense pharmacological applications like antiviral, antidiabetic, anti-inflammatory, and so on. Molecular docking of 30 oxindole derivatives done on the crystallized structure of the protein (COVID-19 Mpro). Methods: The process of docking, interaction, and binding the structure of ligand with protein has executed using Molegro Virtual Docker v.7.0.0 (MVD) and visualized the usage by Molegro Molecular Viewer v.7.0.0 (MMV). Results: Among the 30 derivatives, the outcomes depicted better steric interaction and hydrogen bonding amongst OD-22 ligand, OD-16 ligand, OD-4 ligand, and OD-9 ligand (oxindole derivatives) with COVID-19. In addition to this, the comparative study of these four compounds with existing drugs that are under clinical trials shows comparatively good results in terms of its MolDock scores, H-bonding, and steric interactions. Conclusions: Hence, It is proposed that these four oxin-dole derivatives have good potential as a new drug against coronavirus as possible therapeutic agents.
Journal of Biomolecular Structure and Dynamics
SARS-CoV-2 pandemic has claimed millions of lives across the world. As of June 2020, there is no FDA approved antiviral therapy to eradicate this dreadful virus. In this study, drug re-purposing and computational approaches were employed to identify high affinity inhibitors of SARS-CoV-2 Main protease (3CLpro), Papain-like protease (PLpro) and the receptor domain of Spike protein. Molecular docking on 40 derivatives of standard drugs (Remdesivir, Lopinavir and Theophylline) led to the identification of R10, R2 and L9 as potential inhibitors of 3CLpro, PLpro and Spike protein, respectively. The binding affinity of R10, R2 and L9 towards 3CLpro, PLpro and Spike protein were 4.03 Â 10 6 , 3.72 Â 10 4 and 1.31 Â 10 4 M À1 , respectively. These inhibitors interact with the active site or catalytic amino acid residues of 3CLpro, PLpro and Spike protein. We also examined the stability and dynamic behavior of protein-inhibitor complex by employing molecular dynamics simulation. RMSDs, RMSFs and variation in secondary structure of target proteins alone or in complex with their respective inhibitors were used to ascertain the integrity of proteins' structure during simulation. Moreover, physicochemical and ADMET properties of R10, R2 and L9 along with Remdesivir, Lopinavir and Theophylline were determined. In vitro and In vivo studies are needed to further validate the potential of these derivatives before they can be developed into potential drug molecules.
Heliyon
Isopropyl 1-benzoyl-4-(benzoyloxy)-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (IDPC) was synthesized and characterized via spectroscopic (FT-IR and NMR) techniques. Hirshfeld surface and topological analyses were conducted to study structural and molecular properties. The energy gap (E g), frontier orbital energies (E HOMO , E LUMO) and reactivity parameters (like chemical hardness and global hardness) were calculated using density functional theory with B3LYP/6-311þþG (d,p) level of theory. Molecular docking of IDPC at the active sites of SARS-COVID receptors was investigated. IDPC molecule crystallized in the centrosymmetric triclinic (P1) space group. The topological and Hirshfeld surface analysis revealed that covalent, non-covalent and intermolecular H-bonding interactions, and electron delocalization exist in the molecular framework. Higher binding score (-6.966 kcal/mol) of IDPC at the active site of SARS-COVID main protease compared to other proteases suggests that IDPC has the potential of blocking polyprotein maturation. H-bonding and π-cationic and interactions of the phenyl ring and carbonyl oxygen of the ligand indicate the effective inhibiting potential of the compound against the virus.
Molecular Docking Studies on Synthetic Therapeutic Agents for COVID-19
Chemistry proceedings, 2020
Coronavirus disease (COVID-19) is an infectious disease caused by coronavirus 2 (SARS-CoV-2) which was detected for the first time in Wuhan China in December 2019. The rapid spread of this highly contagious and pathogenic virus led to the declaration of the pandemic by the World Health Organization (WHO) on March 11, 2020. In these conditions, the discovery of new antiviral agents is extremely important. For the development of the anti-SARS-CoV-2 drugs, the fastest way is to find potential molecules from the marketed drugs by molecular docking studies.
International Journal for Research in Applied Science and Engineering Technology IJRASET, 2020
Covid 19 has been the most devastating pandemic of the recent years, affecting 3 million people in about 210 Countries. Entire World is working on inventing a drug for this pandemic. As a major breakthrough, the crystal structure of Covid 19 main protease 3CL Pro or M Pro , which plays a major role in mediating the replication and transcription of the virus , was derived by Jin, Z., Du, X., Xu, Y. et al., paving way for the drug design. The crystal structure of M Pro with a computer aided design inhibitor N (6LU7) has been used as a potential target for drug design in this work. Three possible binding sites were identified for 3CL Pro or M Pro using DEEPSITE, a protein binding pocket predictor. Complimentary Ligand shapes were generated for the SARS CoV2 main protease M Pro , making use of LIGANN, a structure based de novo drug design tool. They are purely structure based designs and do not have any previous history of synthesis or usage. Molecular docking of the new ligands with the target protein 6LU7 was done using iGEMdock. The binding free energy values were calculated. 10 best ligand designs , for each binding site, based on lowest free energy requirement for have been selected for further study. The binding probability for the 10 ligands were calculated using BINDSCOPE, a structure based protein ligand binding predictor. The identical structures for these ligands were identified using Drug bank database. The results were verified with Tanimoto Coefficient calculation. Based on various parameters like free binding energy, binding probability, structural identity and Tanimoto coefficient, top 5 ligand structures have been selected as potential leads for drug discovery.
The novel coronavirus, SARS-CoV-2, has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of a vaccine and potential therapeutics are critically essential. The crystal structure for the main protease (M pro) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CL pro), was recently made available and is considerably similar to the previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, a computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against the 3-chymotrypsin-like cysteine protease (3CL pro) enzyme was accomplished, and indinavir was described as a lead drug with a docking score of −8.824 and a XP Gscore of −9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus, a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound 16 with a docking score of −8.955 adhered to drug-like parameters, and the structure−activity relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular dynamics (MD) simulation analysis performed at 100 ns supported the stability of 16 within the binding pocket. Largely, our results supported that this novel compound 16 binds with domains I and II, and the domain II−III linker of the 3CL pro protein, suggesting its suitability as a strong candidate for therapeutic discovery against COVID-19.
Synthesis and molecular docking study of novel COVID-19 inhibitors
Turkish Journal of Chemistry, 2021
Introduction The most interested subject in 2020 is corona virus disease, which was named as COVID-19 by the WHO (World Health Organization) on the February 11, 2020 [1], This novel coronavirus is called as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by the international virus classification commission. Viruses in the corona family cause diseases in respiratory, gastrointestinal, hepatic, and central nervous system in both humans and animals [2]. Due to the respiratory transmission of SARS-CoV-2 from person to person, it has led to the formation of pandemic conditions in a short time. The world has become familiar with corona virus first with SARS (Severe Acute Respiratory Syndrome) epidemic, and then with the MERS (Middle East Respiratory Syndrome) epidemic [3]. The cause of pneumonia in COVID-19 cases is revealed as unique b-CoV strain [4]. The scientific world does not have an approved treatment specific to SARS-CoV-2. Luckily, it was shown that the novel b-CoV shows 88% similarity to the (SARS)-like coronaviruses, and about 50% to the MERS CoV. Therefore, drugs used for SARS and MERS have come forth again [5]. There are many potential drug candidates for the treatment of COVID-19 such as, oseltamivir [2], lopinavir/ ritonavir [6, 7], nucleoside analogues and nucleotide inhibitors [8] remdesivir [6, 9], tenofovir, ribavirin, sofosbuvir, galidesivir [10] antibiotics [11] and chloroquine and hydroxychloroquine [12,13]. Alternatively, various phytochemicals were used against SARS-CoV-2 virus too. Examples are, belachinal, macaflavanone E and vibsanol B [14], flavone and coumarine derivatives [15], saikosaponins [16], crocin, digitoxigenin, and ß-eudesmol [17], d-viniferin, myricitrin, Taiwan homoflavone A, lactucopicrin 15-oxalate, nymfolide A, afzelin, biorobin, hesperidin and phyllaemblicin B [18], and theophylline derivatives [19]. Hydroxychloroquine, which is mainly used for the treatment of malaria [20] was the first drug to be considered suitable for use in the treatment of COVID-19. On 17 June 2020, WHO announced that the research examining the effects of hydroxychloroquine in the treatment of COVID-19 was cancelled. It has been reported that the drug does not have a positive effect on the mortality rate and duration of hospital stay compared to standard treatments [21]. On July 1, 2020 FDA (Food and Drug Administration) issued a warning stating that hydroxychloroquine causes heart rhythm problems, blood and lymph system disorders, kidney injuries, and liver problems and failure [22]. Remdesivir is an antiviral drug that block viral RNA synthesis of RNA viruses such as SARS and MERS. The antiviral efficacy of the drug has been proven in many in vitro studies [23, 24]. However, it has not been approved for the COVID-19 treatment yet. As the emergency situation continues, FDA has issued an authorization on the use of the drug on hospitalized patients receiving COVID-19 treatment [22].
Applied Biochemistry and Biotechnology
The novel coronavirus disease that arises in the end of 2019 (COVID-19) in Wuhan, China, has rapidly spread over the globe and was considered as a world pandemic. Currently, various antiviral therapies or vaccines are available, and many researches are ongoing for further treatments. Targeting the coronavirus' main protease (key enzyme: 3CLpro) is growing in importance in anti-SARS-CoV-2 drug discovery process. The present study aims at predicting the antiviral activity of two novel compounds using in silico approaches that might become potential leads against SARS-CoV-2. The 3D structures of the new compounds are elucidated by single-crystal X-ray techniques. The interactions between different units of 4 and 5 were emphasized by analyzing their corresponding Hirshfeld surfaces and ESP plots. NBO and FMO analyses were investigated as well. Molecular docking combined with molecular dynamics simulations (MDs) was performed to investigate the binding modes and molecular interactions of 4 and 5 with the amino acids of coronavirus main protease (6LU7) protein. The best docking scores were obtained for both ligands through the major binding interactions via hydrogen/hydrophobic bonds with the key amino acids in the active site: HIS41, CYS145, MET49, MET165, HIS172, and GLU166 amino acids. A MD simulation study was also performed for 100 ns to validate the stability behavior of the main protease 3CLpro-ligand complexes. The MD simulation study successfully confirmed the stability of the ligands in the binding site as potent anti-SARS-CoV-2 (COVID-19) inhibitors. Additionally, MMPBSA energy of both docked complexes was determined as a validation assay of docking and MD simulations to validate compound conformation and interaction stability with 3CLpro. The synthesized compounds might be helpful in the fight against COVID-19 prior to biological activity confirmation in vitro and in vivo.