Spiroindole-containing compounds bearing phosphonate group of potential Mpro-SARS-CoV-2 inhibitory properties
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ABSTRACT:
SUBMITTER: Bekheit M
PROVIDER: S-EPMC10257517 | biostudies-literature | 2023 Jun
REPOSITORIES: biostudies-literature
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Project description:Preventing the biological activity of SARS-CoV-2 main protease using natural compounds is of great interest. In this context, using a combination of AutoDock Vina and fast pulling of ligand simulations, eleven marine fungi compounds were identified that probably play as highly potent inhibitors for preventing viral replication. In particular, four compounds including M15 (3-O-(6-O-α-l-arabinopyranosyl)-β-d-glucopyranosyl-1,4-dimethoxyxanthone), M8 (wailupemycins H), M11 (cottoquinazolines B), and M9 (wailupemycins I) adopted the predicted ligand-binding free energy of -9.87, -9.82, -9.62, and -9.35 kcal mol-1, respectively, whereas the other adopted predicted ligand-binding free energies in the range from -8.54 to -8.94 kcal mol-1. The results were obtained using a combination of Vina and FPL simulations. Notably, although, AutoDock4 adopted higher accurate results in comparison with Vina, Vina is proven to be a more suitable technique for rapidly screening ligand-binding affinity with a large database of compounds since it requires much smaller computing resources. Furthermore, FPL is better than Vina to classify inhibitors upon ROC-AUC analysis.
| S-EPMC9034196 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a dreaded pandemic in lack of specific therapeutic agent. SARS-CoV-2 Mpro, an essential factor in viral pathogenesis, is recognized as a prospective therapeutic target in drug discovery against SARS-CoV-2. To tackle this pandemic, Food and Drug Administration-approved drugs are being screened against SARS-CoV-2 Mpro via in silico and in vitro methods to detect the best conceivable drug candidates. However, identification of natural compounds with anti-SARS-CoV-2 Mpro potential have been recommended as rapid and effective alternative for anti-SARS-CoV-2 therapeutic development. Thereof, a total of 653 natural compounds were identified against SARS-CoV-2 Mpro from NP-lib database at MTi-OpenScreen webserver using virtual screening approach. Subsequently, top four potential compounds, i.e. 2,3-Dihydroamentoflavone (ZINC000043552589), Podocarpusflavon-B (ZINC000003594862), Rutin (ZINC000003947429) and Quercimeritrin 6"-O-L-arabinopyranoside (ZINC000070691536), and co-crystallized N3 inhibitor as reference ligand were considered for stringent molecular docking after geometry optimization by DFT method. Each compound exhibited substantial docking energy >-12 kcal/mol and molecular contacts with essential residues, including catalytic dyad (His41 and Cys145) and substrate binding residues, in the active pocket of SARS-CoV-2 Mpro against N3 inhibitor. The screened compounds were further scrutinized via absorption, distribution, metabolism, and excretion - toxicity (ADMET), quantum chemical calculations, combinatorial molecular simulations and hybrid QM/MM approaches. Convincingly, collected results support the potent compounds for druglikeness and strong binding affinity with the catalytic pocket of SARS-CoV-2 Mpro. Hence, selected compounds are advocated as potential inhibitors of SARS-CoV-2 Mpro and can be utilized in drug development against SARS-CoV-2 infection.
| S-EPMC7929395 | biostudies-literature
Project description:Concerned organizations and individuals are fully engaged in seeking appropriate measures towards managing Severe Acute Respiratory Syndrome Coronavirus 2 (SAR-CoV-2) infection because of the unprecedented economic and health impact. SAR-CoV-2 Main protease (SARS-CoV-2 Mpro) is unique to the survival and viability of the virus. Therefore, inhibition of Mpro can block the viral propagation. Thirty (30) derivatives were built by changing the glucosides in the Meta and para position of quercetin and isohamnetin. Molecular docking analysis was used for the screening of the compounds. Dynamics simulation was performed to assess the stability of the best pose docked complex. Molecular mechanics binding free energy calculation was done by Molecular Mechanics/Poisson-Boltzmann Surface Area (MMPBSA). Overall analysis showed that the compounds are allosteric inhibitors of SARS-CoV-2 Mpro. Dynamic simulation analysis established the stability of Mpro-ISM-1, Mpro-ISD-3, Mpro-IST-2, Mpro-QM-2, and Mpro-QD-6 complexes with a maximum of 7 hydrogen bonds involved in their interaction. The MMPBSA binding free energies for ISM-1, ISD-3, IST-2, QM-2, and QD-6 were -92.47 ± 9.06, -222.27 ± 32.5, 180.72 ± 47.92, 156.46 ± 49.88 and -93.52 ± 48.75 kcal/mol respectively. All the compounds showed good pharmacokinetic properties, while only ISM-1 inhibits hERG and might be cardio-toxic. Observations in this study established that the glucoside position indeed influenced the affinity for SARS-CoV-2 Mpro. The study also suggested the potentials of ISD-3, QM-2 and QD-6 as potent inhibitors of the main protease, further experimental and clinical studies are however necessary to validate and establish the need for further drug development processes. Therefore, future studies will be on the chemical synthesis of the compounds and investigation of the in-vitro inhibition of SARS-CoV-2.
| S-EPMC9837157 | biostudies-literature
Project description:Cancer is one of the most significant health challenges worldwide. Various techniques, tools and therapeutics/materials have been developed in the last few decades for the treatment of cancer, together with great interest, funding and efforts from the scientific society. However, all the reported studies and efforts seem insufficient to combat the various types of cancer, especially the advanced ones. The overexpression of tyrosine kinases is associated with cancer proliferation and/or metastasis. VEGF, an important category of tyrosine kinases, and its receptors (VEGFR) are hyper-activated in different cancers. Accordingly, they are known as important factors in the angiogenesis of different tumors and are considered in the development of effective therapeutic approaches for controlling many types of cancer. In this case, targeted therapeutic approaches are preferable to the traditional non-selective approaches to minimize the side effects and drawbacks associated with treatment. Several indole-containing compounds have been identified as effective agents against VEGFR. Herein, we present a summary of the recent indolyl analogs reported within the last decade (2012-2023) with potential antineoplastic and VEGFR inhibitory properties. The most important drugs, natural products, synthesized potent compounds and promising hits/leads are highlighted. Indoles functionalized and conjugated with various heterocycles beside spiroindoles are also considered.
| S-EPMC10866129 | biostudies-literature
Project description:To date, the COVID-19 pandemic has still been infectious around the world, continuously causing social and economic damage on a global scale. One of the most important therapeutic targets for the treatment of COVID-19 is the main protease (Mpro) of SARS-CoV-2. In this study, we combined machine-learning (ML) model with atomistic simulations to computationally search for highly promising SARS-CoV-2 Mpro inhibitors from the representative natural compounds of the National Cancer Institute (NCI) Database. First, the trained ML model was used to scan the library quickly and reliably for possible Mpro inhibitors. The ML output was then confirmed using atomistic simulations integrating molecular docking and molecular dynamic simulations with the linear interaction energy scheme. The results turned out to show that there was evidently good agreement between ML and atomistic simulations. Ten substances were proposed to be able to inhibit SARS-CoV-2 Mpro. Seven of them have high-nanomolar affinity and are very potential inhibitors. The strategy has been proven to be reliable and appropriate for fast prediction of SARS-CoV-2 Mpro inhibitors, benefiting for new emerging SARS-CoV-2 variants in the future accordingly.
| S-EPMC9950021 | biostudies-literature
Project description:The worldwide pandemic of coronavirus disease 2019 (COVID-19) along with the various newly discovered major SARS-CoV-2 variants, including B.1.1.7, B.1.351, and B.1.1.28, constitute the Variant of Concerns (VOC). It's difficult to keep these variants from spreading over the planet. As a result of these VOCs, the fifth wave has already begun in several countries. The rapid spread of VOCs is posing a serious threat to human civilization. There is currently no specific medicine available for the treatment of COVID-19. Here, we present the findings of methods that used a combination of structure-assisted drug design, virtual screening, and high-throughput screening to swiftly generate lead compounds against Mpro protein of SARs-CoV-2. Therapeutics, in addition to vaccinations, are an essential element of the healthcare response to COVID-19's persistent threat. In the current study, we designed the efficient compounds that may combat all emerging variants of SARs-CoV-2 by targeting the common Mpro protein. The present study was aimed to discover new compounds that may be proposed as new therapeutic agents to treat COVID-19 infection without any adverse effects. For this purpose, a computational-based virtual screening of 352 in-house synthesized compounds library was performed through molecular docking and Molecular Dynamics (MD) simulation approach. As a result, four novel potent compounds were successfully shortlisted by implementing certain pharmacological, physiological, and ADMET criteria i.e., compounds 3, 4, 21, and 22. Furthermore, MD simulations were performed to evaluate the stability and dynamic behavior of these compounds with Mpro complex for about 30 ns. Eventually, compound 22 was found to be highly potent against Mpro protein and was further evaluated by applying 100 ns simulations. Our findings showed that these shortlisted compounds may have potency to treat the COVID-19 infection for which further experimental validation is proposed as part of a follow-up investigation.
| S-EPMC9635257 | biostudies-literature
Project description:Graphical abstract The SARS-CoV-2 main protease (Mpro) has been chosen as a conserved molecular target to develop broad-spectrum antiviral drugs. Using molecular docking and molecular dynamics (MD) simulations, a total of 5600 natural compounds available for virtual screening were tested to identify potential inhibitors of SARS-CoV-2 Mpro. As a result, three natural compounds (pentagalloylglucose, malonylawobanin and gnetin E dihydride) were found to be potential inhibitors of SARS-CoV-2, which confirms the theoretical and practical significance of this approach for the design of SARS-CoV-2 inhibitors.
| S-EPMC9141681 | biostudies-literature
Project description:A series of 1″-(alkylsulfonyl)-dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidine]-2,4″-diones 6a‒o has been synthesized through regioselective multi-component azomethine dipolar cycloaddition reaction of 1-(alkylsulfonyl)-3,5-bis(ylidene)-piperidin-4-ones 3a‒h. X-ray diffraction studies (6b‒d,h) confirmed the structures. The majority of the synthesized analogs reveal promising antiproliferation properties against a variety of human cancer cell lines (MCF7, HCT116, A431 and PaCa2) with good selectivity index towards normal cell (RPE1). Some of the synthesized agents exhibit potent inhibitory properties against the tested cell lines with higher efficacies than the standard references (sunitinib and 5-fluorouracil). Compound 6m is the most potent. Multi-targeted inhibitory properties against EGFR and VEGFR-2 have been observed for the synthesized agents. Flow cytometry supports the antiproliferation properties and shows the tested agents as apoptosis and necrosis forming. Vero cell viral infection model demonstrates the anti-SARS-CoV-2 properties of the synthesized agents. Compound 6f is the most promising (about 3.3 and 4.8 times the potency of the standard references, chloroquine and hydroxychloroquine). QSAR models explain and support the observed biological properties.
| S-EPMC9380671 | biostudies-literature
Project description:Umbelliferone is a member of the coumarin family of compounds which are known for diverse pharmacological activity including in targets relevant to Alzheimers disease, AD. The toxicity associated with some forms of the amyloid protein, Aβ, and the role of Zn2+ (and other biometals) dyshomeostasis in this, are of great interest in AD and make metal ionophore capability desirable in so called multi target drug ligands MTDLs. A new series of umbelliferyloxymethyl phosphonic acid diethylester compounds (umbelliferyloxymethyl phosphonates) bearing a phosphonate at the 7-position (compounds 1, 3-6), hydrolysis products 2, 2a and 2b from 1 and analogues 7 and 8 of 1 with 7-O to 7-S and 1-O to 1-NH substitutions, are reported. Single crystal X-ray structures of compounds 1, 2 and 2a were determined. In terms of neuroprotective properties, the compounds 1, 2, 3, 4, 5 and 6 at 1 μM concentration, inhibited the toxicity of Aβ1-42 (Aβ42) in both toxic Amyloid Derived Diffusible Ligand (ADDL) and fibrillar (fibril) forms towards rat hippocampal cells. Compound 7 displayed cytotoxicity and 8 failed to inhibit Aβ42 toxicity. Concerning compound-metal ionophore activity (assessed using chemical experiments), despite weak binding to Zn2+ determined from 31P NMR titration of 1 and 2 by ZnCl2, compounds 1, 3, 4, 5 and 6 demonstrated ionophore assisted partition of Zn2+ from water to octanol at micromolar concentrations with efficacy on a par with or better than the chelator MTDL clioquinol (5-chloro-7-iodo-8-hydroxyquinoline). Partition was assessed using furnace Atomic Absorption Spectroscopy (AAS). In further experiments interaction of compound 1 with Zn2+ or it's pathways was inferred by (i) delayed fluorescence response with added Zn2+ in cells treated with FluoZin-3 and (ii) by suppression of Zn2+ promoted aggregation of Aβ42.
| S-EPMC8631114 | biostudies-literature
Project description:Hyperactivation of the complement system, a major component of innate immunity, has been recognized as one of the core clinical features in severe covid-19 patients. However, how the virus escapes the targeted elimination by the network of activated complement pathways still remains an enigma. Here, we identified SARS-CoV-2-encoded ORF8 protein as one of the major binding partners of human complement C3/C3b components and their metabolites. Our results demonstrated that preincubation of ORF8 with C3/C3b in the fluid phase has two immediate functional consequences in the alternative pathway; this preincubation inhibits factor I-mediated proteolysis and blocks factor B zymogen activation into active Bb. ORF8 binding results in the occlusion of both factor H and factor B from C3b, rendering the complexes resistant to factor I-mediated proteolysis and inhibition of pro-C3-convertase (C3bB) formation, respectively. We also confirmed the complement inhibitory activity of ORF8 in our hemolysis-based assay, where ORF8 prevented human serum-induced lysis of rabbit erythrocytes with an IC50 value of about 2.3 μM. This inhibitory characteristic of ORF8 was also supported by in-silico protein-protein docking analysis, as it appeared to establish primary interactions with the β-chain of C3b, orienting itself near the C3b CUB (C1r/C1s, Uegf, Bmp1) domain like a peptidomimetic compound, sterically hindering the binding of essential cofactors required for complement amplification. Thus, ORF8 has characteristics to act as an inhibitor of critical regulatory steps in the alternative pathway, converging to hasten the decay of C3-convertase and thereby, attenuating the complement amplification loop.
| S-EPMC9851726 | biostudies-literature