Virtual Screening of Natural Metabolites and Antiviral Drugs with Potential Inhibitory Activity against 3CL-PRO and PL-PRO

Contreras‐Puentes, Neyder; Alvíz‐Amador, Antistio

doi:10.13005/bpj/1962

Cited by 12 publications

(7 citation statements)

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“…Molecular docking is an in silico approach with ability to screen and identify potential drug molecules from large and massive bioactive compound libraries. Currently, several molecular docking studies were carried out against SARS-CoV-2 receptors with some selected bioactive compounds (Table 1) and have been able to identify few potential compounds drug molecules effective against targeted receptors of COVID-19 [7,[9][10][11][12][13][14]. However, most of these docking studies relied on structure-based drug design (SBDD), as well as similarity searching and quantitative structure-activity relationship (QSAR) modeling [8].…”

Section: Introductionmentioning

confidence: 99%

Identification of phytocompounds from Houttuynia cordata Thunb. as potential inhibitors for SARS-CoV-2 replication proteins through GC–MS/LC–MS characterization, molecular docking and molecular dynamics simulation

et al. 2021

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The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a massive viral disease outbreak of international concerns. The present study is mainly intended to identify the bioactive phytocompounds from traditional antiviral herb Houttuynia cordata Thunb. as potential inhibitors for three main replication proteins of SARS-CoV-2, namely Main protease (Mpro), Papain-Like protease (PLpro) and ADP ribose phosphatase (ADRP) which control the replication process. A total of 177 phytocompounds were characterized from H. cordata using GC-MS/LC-MS and they were docked against three SARS-CoV-2 proteins (receptors), namely Mpro, PLpro and ADRP using Epic, LigPrep and Glide module of Schrödinger suite 2020-3. During docking studies, phytocompounds (ligand) 6-Hydroxyondansetron (A104) have demonstrated strong binding affinity toward receptors Mpro (PDB ID 6LU7) and PLpro (PDB ID 7JRN) with G-score of − 7.274 and − 5.672, respectively, while Quercitrin (A166) also showed strong binding affinity toward ADRP (PDB ID 6W02) with G-score -6.788. Molecular Dynamics Simulation (MDS) performed using Desmond module of Schrödinger suite 2020-3 has demonstrated better stability in the ligand-receptor complexes A104-6LU7 and A166-6W02 within 100 ns than the A104-7JRN complex. The ADME-Tox study performed using SwissADMEserver for pharmacokinetics of the selected phytocompounds 6-Hydroxyondansetron (A104) and Quercitrin (A166) demonstrated that 6-Hydroxyondansetron passes all the required drug discovery rules which can potentially inhibit Mpro and PLpro of SARS-CoV-2 without causing toxicity while Quercitrin demonstrated less drug-like properties but also demonstrated as potential inhibitor for ADRP. Present findings confer opportunities for 6-Hydroxyondansetron and Quercitrin to be developed as new therapeutic drug against COVID-19.Sanjib Kumar Das and Saurov Mahanta have contributed equally to this work.

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Section: Introductionmentioning

confidence: 99%

Identification of phytocompounds from Houttuynia cordata Thunb. as potential inhibitors for SARS-CoV-2 replication proteins through GC–MS/LC–MS characterization, molecular docking and molecular dynamics simulation

et al. 2021

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“…A database of 1,702 approved drugs (i.e., currently in postmarketing surveillance trial) and 688 compounds that have reached phase III clinical trials was docked to the crystal structure of PLpro [PDB ID 6WX4 (Rut et al, 2020 )]. Noteworthy, the high resolution (1.66 Å) and the presence of a cocrystallized peptide inhibitor make this PLpro structure, released on the May 20, 2020, particularly suitable for docking-based VS campaigns that to date have been only performed with PLpro homology models (Amin et al, 2020 ; Contreras-Puentes and Alvíz-Amador, 2020 ) or apo structures (Quimque et al, 2020 ). First, all the compounds were ranked according to their docking scores, and the 500 top-ranking molecules were kept for further evaluation.…”

Section: Resultsmentioning

confidence: 99%

Repurposing Known Drugs as Covalent and Non-covalent Inhibitors of the SARS-CoV-2 Papain-Like Protease

et al. 2020

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In the absence of an approved vaccine, developing effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antivirals is essential to tackle the current pandemic health crisis due to the coronavirus disease 2019 (COVID-19) spread. As any traditional drug discovery program is a time-consuming and costly process requiring more than one decade to be completed, in silico repurposing of existing drugs is the preferred way for rapidly selecting promising clinical candidates. We present a virtual screening campaign to identify covalent and non-covalent inhibitors of the SARS-CoV-2 papain-like protease (PLpro) showing potential multitarget activities (i.e., a desirable polypharmacology profile) for the COVID-19 treatment. A dataset including 688 phase III and 1,702 phase IV clinical trial drugs was downloaded from ChEMBL (version 27.1) and docked to the recently released crystal structure of PLpro in complex with a covalently bound peptide inhibitor. The obtained results were analyzed by combining protein–ligand interaction fingerprint similarities, conventional docking scores, and MM-GBSA–binding free energies and allowed the identification of some interesting candidates for further in vitro testing. To the best of our knowledge, this study represents the first attempt to repurpose drugs for a covalent inhibition of PLpro and could pave the way for new therapeutic strategies against COVID-19.

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“…Although molecules obtained from virtual screens have previously been deposited in the literature for prospective testing against PL pro [ 84 , 85 , 86 , 87 , 88 ], these were mainly docking studies, and we could not find any paper where a ligand-based virtual screen of such scale had been performed against GRL-0617 before docking. Additionally, and in contrast to our work, the docking had commonly been performed against the PL pro catalytic site and not the GRL-0617 binding site, which is distinctly different.…”

Section: Discussionmentioning

confidence: 99%

Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

2021

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The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS coronaviruses. Importantly, lessons learned from the SARS outbreak of 2002-2004, caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), can be applied to current drug discovery ventures. SARS-CoV-1 and SARS-CoV-2 both possess two cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), which play a significant role in facilitating viral replication, and are important drug targets. The non-covalent inhibitor, GRL-0617, which was found to inhibit replication of SARS-CoV-1, and more recently SARS-CoV-2, is the only PLpro inhibitor co-crystallised with the recently solved SARS-CoV-2 PLpro crystal structure. Therefore, the GRL-0617 structural template and pharmacophore features are instrumental in the design and development of more potent PLpro inhibitors. In this work, we conducted scaffold hopping using GRL-0617 as a reference to screen over 339,000 ligands in the chemical space using the ChemDiv, MayBridge, and Enamine screening libraries. Twenty-four distinct scaffolds with structural and electrostatic similarity to GRL-0617 were obtained. These proceeded to molecular docking against PLpro using the AutoDock tools. Of two compounds that showed the most favourable predicted binding affinities to the target site, as well as comparable protein-ligand interactions to GRL-0617, one was chosen for further analogue-based work. Twenty-seven analogues of this compound were further docked against the PLpro, which resulted in two additional hits with promising docking profiles. Our in silico pipeline consisted of an integrative four-step approach: (1) ligand-based virtual screening (scaffold-hopping), (2) molecular docking, (3) an analogue search, and, (4) evaluation of scaffold drug-likeness, to identify promising scaffolds and eliminate those with undesirable properties. Overall, we present four novel, and lipophilic, scaffolds obtained from an exhaustive search of diverse and uncharted regions of chemical space, which may be further explored in vitro through structure-activity relationship (SAR) studies in the search for more potent inhibitors. Furthermore, these scaffolds were predicted to have fewer off-target interactions than GRL-0617. Lastly, to our knowledge, this work contains the largest ligand-based virtual screen performed against GRL-0617.

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Virtual Screening of Natural Metabolites and Antiviral Drugs with Potential Inhibitory Activity against 3CL-PRO and PL-PRO

Cited by 12 publications

References 0 publications

Identification of phytocompounds from Houttuynia cordata Thunb. as potential inhibitors for SARS-CoV-2 replication proteins through GC–MS/LC–MS characterization, molecular docking and molecular dynamics simulation

Identification of phytocompounds from Houttuynia cordata Thunb. as potential inhibitors for SARS-CoV-2 replication proteins through GC–MS/LC–MS characterization, molecular docking and molecular dynamics simulation

Repurposing Known Drugs as Covalent and Non-covalent Inhibitors of the SARS-CoV-2 Papain-Like Protease

Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

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