Potential drugs against COVID-19 revealed by gene expression profile, molecular docking and molecular dynamic simulation.
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ABSTRACT:
SUBMITTER: Cava C
PROVIDER: S-EPMC8293696 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The COVID-19 pandemic outbreak demands the designing of potential drugs as there is no specific treatment available. Thanks to their safety and effectiveness, phytochemicals have been used to treat various diseases, including antiviral therapeutics. Molecular docking is a simple, quick, and effective way to screen a variety of molecules for structure-based drug design. Here, we investigate molecular docking experiments on compounds present in plant species, Cocculus hirsutus and Rhodiola rosea and show their potential for the treatment of COVID-19. Almost all the components showed higher binding affinity than the built-in ligand, and those with significantly higher binding affinity were explored further. Molecular mechanics-based generalized born surface area calculations were used to re-rank the top candidates, rhodionidin and cocsoline, and their stability in association with viral protease was confirmed. Density functional theory was used for detailed investigations of the geometries, and electrical properties of rhodionidin and cocsoline. Using the frontier molecular orbitals method, the charge transfer within the molecule was calculated. Chemical reactivity and intermolecular interactions were studied using molecular electrostatic potential maps. These in silico discoveries will simulate the identification of powerful COVID-19 inhibitors, and similar research is likely to make a significant contribution to antiviral drug discovery.Supplementary informationThe online version contains supplementary material available at 10.1007/s11224-022-01982-4.
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Project description:Human Topoisomerase I (hTop1p) is a ubiquitous enzyme that relaxes supercoiled DNA through a conserved mechanism involving transient breakage, rotation, and binding. Htop1p is the molecular target of the chemotherapeutic drug camptothecin (CPT). It causes the hTop1p-DNA complex to slow down the binding process and clash with the replicative machinery during the S phase of the cell cycle, forcing cells to activate the apoptotic response. This gives hTop1p a central role in cancer therapy. Recently, two artesunic acid derivatives (compounds c6 and c7) have been proposed as promising inhibitors of hTop1p with possible antitumor activity. We used several computational approaches to obtain in silico confirmations of the experimental data and to form a comprehensive dynamic description of the ligand-receptor system. We performed molecular docking analyses to verify the ability of the two new derivatives to access the enzyme-DNA interface, and a classical molecular dynamics simulation was performed to assess the capacity of the two compounds to maintain a stable binding pose over time. Finally, we calculated the noncovalent interactions between the two new derivatives and the hTop1p receptor in order to propose a possible inhibitory mechanism like that adopted by CPT.
| S-EPMC9737192 | biostudies-literature
Project description:Recently, scary viral pneumonia is known as (COVID-19) has swept the whole world. The new virus strain designated as SARS-CoV-2 belonging to the coronavirus family. Although the current medical research directed towards the development of a novel therapeutic agent, no anti-viral drug approved until now. On the medical scale, the development of an approved drug is a time-consuming process, so research is directed towards screening of ligands and drugs multimodal structure-based-design and then docked to the main viral protease to investigate the active binding sites. The bioinformatic approaches used to evaluate the competence of a comprehensive range of ligands and drugs before their clinical implementation. In this study, a computational approach through molecular docking simulation is conducted for screening the antiviral activity of drugs, natural sources, and inhibitory compounds against the SARS-CoV-2 genome. The main virus protease was collected from a Protein Data Bank (PDB# 6YB7) and docked with a sequence of 19 approved antiviral drugs, 10 natural inhibitory ligands against COVID-19 downloaded from PubChem, in addition to 10 natural sources optimized for Escherichia coli BL21 (DE3) to identify the antiviral activity of these candidates against COVID-19. The docking results were promised and indicated that the reported ligands can firmly bind to the SARS-CoV-2 main protease and leads to inhibition of its infectious impact.
| S-EPMC7399655 | biostudies-literature
Project description:Covid-19 is a beta-coronavirus that was first identified during the Wuhan COVID-19 epidemic in 2019. This study is focused on the quantum descriptors of the proposed antiviral drugs, molecular docking, and dynamics simulation with the main protease of coronavirus. Such drugs are Baloxavir, Chloroquine, Avigan, Plaquenil, oseltamivir, Remdesivir, Arbidol, and Sofosbuvir were used for comparison. Density functional theory (DFT) may help find the relevancy of quantum chemical descriptors to explain the potential antiviral activity, Some quantum descriptors such as ΔE; the energy gap, η; global hardness, S; global softness, I: ionization potential, A: electron affinity, χ: absolute electronegativity, ω; ΔE Back-donation; the back donation were calculated based on EHOMO; energy of the highest occupied molecular orbital, and ELUMO; energy of the lowest unoccupied molecular orbital. Fukui indices (f+, f−); for local nucleophilic and electrophilic attacks are investigated for the investigated antiviral drugs. The reported genomic sequence of Covid-19 main protease in complex with an inhibitor N3 (DOI: https://doi.org//10.2210/pdb6LU7/pdb) was used as a precursor for docking with the selected drugs after removing the attached inhibitors N3 and water. Molecular docking was performed using Autodock 4.2, with the Lamarckian Genetic Algorithm, and was analyzed by Autodock 1.5.6 and Pymol version 1.7.4.5 Edu, However, further research is necessary to investigate their potential medicinal use.
| S-EPMC7826048 | biostudies-literature
Project description: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 SciFinder® 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-Mpro was found to have minimum binding energy of -10.26 kcal/mol and a general energy balance, calculated by the quantum mechanical analysis, of -8.63 eV. MD simulation and MMGBSA calculations confirmed that the derivatives E38 and E40 have high binding energies of -63.47 ± 3 and -63.31 ± 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.Communicated by Ramaswamy H. Sarma.
| S-EPMC7832388 | biostudies-literature
Project description:Pandemic COVID-19 infections have spread throughout the world. There is no effective treatment against this disease. Viral RNA-dependent RNA polymerase (RdRp) catalyzes the replication of RNA from RNA and the main protease (Mpro) has a role in the processing of polyproteins that are translated from the RNA of SARS-CoV-2, and thus these two enzymes are strong candidates for targeting by anti-viral drugs. Small molecules such as lopinavir and favipiravir significantly inhibit the activity of Mpro and RdRp in vitro. Studies have shown that structurally modified lopinavir, favipiravir, and other similar compounds can inhibit COVID-19 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). In this study, lopinavir and its structurally similar compounds were chosen to bind the main protease, and favipiravir was chosen to target RNA-dependent RNA polymerase. Molecular docking and the quantitative structure-activity relationships (QSAR) study revealed that the selected candidates have favorable binding affinity but less druggable properties. To improve the druggability, four structural analogues of lopinavir and one structural analogue of favipiravir was designed by structural modification. Molecular interaction analyses have displayed that lopinavir and favipiravir analogues interact with the active site residues of Mpro and RdRp, respectively. Absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, medicinal chemistry profile, and physicochemical features were shown that all structurally modified analogues are less toxic and contain high druggable properties than the selected candidates. Subsequently, 50 ns molecular dynamics simulation of the top four docked complexes demonstrated that CID44271905, a lopinavir analogue, forms the most stable complex with the Mpro. Further MMPBSA analyses using the MD trajectories also confirmed the higher binding affinity of CID44271905 towards Mpro. In summary, this study demonstrates a new way to identify leads for novel anti-viral drugs against COVID-19. Communicated by Ramaswamy H. Sarma.
| S-EPMC7754938 | biostudies-literature
Project description:The 2019-nCoV has triggered a global public health emergency due to its rapid spread, resulting in a pandemic situation. Because of its ability to bind with the host cell receptor ACE-2, the spike protein of the 2019-nCoV is a critical factor in viral infection. The current study aims to investigate the molecular-docking of the spike protein (6VXX) using PyRx for FDA-approved drugs available for the treatment of SARS-1 and MERS, with the hypothesis that these drugs could be suggested for the treatment of 2019-nCoV or not. A phylogenetic analysis of 2019-nCoV in relation to SARS-1 and MERS confirmed the validation. The positive result urged the Multiple Sequence Alignment analysis of the top five affected countries, with China serving as a control, using WHO available reference data to determine the rate of mutant variation. The docking results revealed that the top ten drugs with the highest binding affinity rate are also used for Hepatitis-C virus treatment, and the Molecular Dynamic Simulation was carried out for the drug Paritaprevir, which had the highest binding affinity rate, using Gromacs. The results indicated that the drug Paritaprevir could be used as a potential target against the 2019-nCoV Spike protein. Graphical abstract Image 1
| S-EPMC9197568 | biostudies-literature
Project description:Background and aimThe present study intends to investigate COVID-19 by targeting their main proteins with 17 selected drugs used for treating Oral Lichen Planus (OLP) which is a chronic muco-cutaneous disorder. Here, an attempt is made to gain better insight into the structure of various drugs targeting specific proteins which will be helpful in developing drugs useful for therapeutic and preventive measures.MethodIn silico studies, molecular docking and molecular dynamic simulations were performed to repurpose the therapeutic drugs (n = 17) which were used to treat OLP against COVID-19. In addition, the maximum binding affinities of the key protein spike glycoprotein, main-protease (Mpro) of coronavirus, and Angiotensin-Converting Enzyme-2 (ACE-2) in the human body were evaluated with the selected drugs.ResultsEpigallocatechin-3-gallate (EGCG) showed the highest docking values among the drugs selected for repurposing. Among the target proteins, EGCG has shown maximum binding affinity with ACE-2 receptor. Further, according to the molecular dynamic simulation studies, EGCG has shown the least conformational fluctuations with Mpro.ConclusionEGCG can be a potential inhibitor drug which can bind with ACE-2 receptor thus inhibiting the interaction of mainly Mpro protein and spike glycoprotein of SARS-CoV-2.Relevance for patientsEGCG, a natural compound shows antiviral potential having considerably high affinity and stability with SARS-CoV-2. It might be further employed as a lead drug against selective inhibitors of SARS-CoV-2 for the therapeutic management of COVID-19 patients after necessary clinical trials.
| S-EPMC9036082 | biostudies-literature
Project description:We selected fifty one drugs already known for their potential disease treatment roles in various studies and subjected to docking and molecular docking simulation (MDS) analyses. Five of them showed promising features that are discussed and suggested as potential candidates for repurposing for COVID-19. These top five compounds were boswellic acid, pimecrolimus, GYY-4137, BMS-345541 and triamcinolone hexacetonide that interacted with the chosen receptors 1R42, 4G3D, 6VW1, 6VXX and 7MEQ, respectively with binding energies of -9.2 kcal/mol, -9.1 kcal/mol, -10.3 kcal/mol, -10.1 kcal/mol and -8.7 kcal/mol, respectively. The MDS studies for the top 5 best complexes revealed binding features for the chosen receptor, human NF-kappa B transcription factor as an important drug target in COVID-19-based drug development strategies.
| S-EPMC10560309 | biostudies-literature
Project description:Human Coronavirus (COVID-19) is a worldwide pandemic of 2019-20 that was emerged in China in December 2019. More than 37,000deaths with7, 84, 440confirmed cases has been reported from around 200 different countries has been reported till now and the number is increasing every second. The spread is said to be through human to human transmission via close contact or respiratory droplets produced when people cough or sneeze. No treatment for the illness has been approved yet. The urgent need is to find solution to this growing problem that has affected the whole mankind. World Health Organisation (WHO) as well as US Food and Drug Administration (FDA) are continuously working to find the solution. In the same line they have proposed many potent drugs that may have efficiency against the newly emerged viral infection. To support the efforts the present study is designed to carry out the in silico analysis viz. Docking studies of around 16drugs recently recommended by US FDA by observing the interaction of test molecules with SARS proteinase.
| S-EPMC7832574 | biostudies-literature