Not One, But Five: Virtual Screening-Driven Drug Discovery of SARS-CoV2 Enzyme Inhibitors Targeting Viral Attachment, Replication and Post-Translational Infection Mechanisms

Quimque, Mark Tristan J.; Notarte, Kin Israel; Fernández, Raquel Martínez; Mendoza, Mark Andrew O.; Liman, Rhenz Alfred D.; Lim, Justin Allen K.; Pilapil, Luis Agustin E.; Ong, Jehiel Karsten H.; Pastrana, Adriel; Macabeo, Allan Patrick G.

doi:10.26434/chemrxiv.12170424.v1

Cited by 4 publications

(2 citation statements)

References 19 publications

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“…A database of 1702 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 co-crystallized peptide inhibitor make this PLpro structure, released on the 20 th of May 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). Firstly, all the compounds were ranked according to their docking scores and the 500 top ranking molecules were kept for further evaluation.…”

Section: Candidates For Non-covalent Plpro Inhibitionmentioning

confidence: 99%

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

Delre¹,

Caporuscio²,

Mangiatordi

2020

Preprint

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In the absence of an approved vaccine, developing effective SARS-CoV-2 antivirals is essential to tackle the current pandemic health crisis due to the 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. Herein we present a virtual screening campaign to identify covalent and non-covalent inhibitors of the SARS-CoV-2 papain-like protease (PLpro) showing potential multi-target activities for the COVID-19 treatment. A dataset including 688 phase III and 1702 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 MMGBSA 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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Section: Candidates For Non-covalent Plpro Inhibitionmentioning

confidence: 99%

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

Delre¹,

Caporuscio²,

Mangiatordi

2020

Preprint

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“…Senyawa norquinadoline A menempel erat ke situs pengikatan PLpro, sebagian besar distabilkan oleh gaya van der Waals. Dua ikatan-H semakin memperkuat interaksinya dengan enzim, khususnya antara oksigen karbonil dari inti pyrazinoquinozolinedione dengan asam amino Lys711 dan Arg712 (Quimque et al, 2020). Senyawa quanidoline B yang berasal dari kapang endofit yang sama dengan norquinadoline A. Senyawa quanidoline B menempel ke situs pengikatan protein RNA-directed RNA polymerase (RdRp) adalah akibat peran serta dari dua bagian tertentu.…”

Section: Setelah Berhasilunclassified

Kapang endofit sebagai sumber senyawa aktif antivirus yang menjanjikan: Suatu Kajian Pustaka

Septiana

2020

JBIOUNUD

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Infeksi virus masih menjadi masalah di seluruh negara di dunia. Vaksinasi dan penggunaan obat-obatan antivirus masih terus dilakukan sebagai upaya untuk menanggulangi infeksi virus. Kemunculan serotipe virus baru yang resisten terhadap obat antivirus yang ada telah meningkatkan usaha pencarian senyawa antivirus baru dari alam. Kapang endofit merupakan salah satu sumber senyawa antivirus yang sangat melimpah di alam. Beberapa senyawa antivirus yang aktif terhadap beberapa jenis virus penyebab infeksi pada manusia telah diisolasi dari kapang endofit. Senyawa emodin dari kapang endofit Aspergillus versicolor, aspergillipeptides D dari Aspergillus sp., dan altertoxin V dari Alternaria tenuissima masing-masing memiliki aktivitas antivirus terhadap virus hepatitis C, herpes, dan HIV melalui pengujian secara in vitro. Sedangkan senyawa katekin dari Annulohypoxylon ilanense, norquinadoline A dari Cladosporium sp., dan isochaetochromin D1 dari Fusarium sp. memiliki aktivitas penghambatan terhadap SARS-CoV-2 secara in silico. Pengembangan senyawa aktif antivirus dari kapang endofit perlu ditingkatkan. Pengembangan meliputi pemilihan metode isolasi senyawa aktif yang optimal, penelitian lebih lanjut tentang mekanisme kerja senyawa antivirus, pengujian secara in vivo hingga uji pre klinis dan klinis. Pengembangan senyawa antivirus dari kapang endofit yang optimal diharapkan akan menghasilkan obat antivirus baru yang lebih efektif dalam pengobatan terhadap infeksi virus.

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Docking and in silico toxicity assessment of Arthrospira compounds as potential antiviral agents against SARS-CoV-2

Petit¹,

Vernès²,

Cadoret³

2021

J Appl Phycol

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A race is currently being launched as a result of the international health situation. This race aims to find, by various means, weapons to counter the Covid-19 pandemic now widespread on all continents. The aquatic world and in particular that of photosynthetic organisms is regularly highlighted but paradoxically little exploited in view of the tremendous possibilities it offers. Computational tools allow not only to clear the existence and activity of many molecules but also to model their relationships with receptors identified in potential hosts. On a routine basis, our laboratory carries out a research activity on functionalities of molecules derived from algae using in silico tools. We have implemented our skills in algae biology and in modeling, as tests in order to identify molecules expressed by the genus Arthrospira showing an antiviral potential and more particularly anti-SARS-CoV-2. Using consensus docking and redocking with Autodock Vina and SwissDock, we were able to identify several promising molecules from Arthrospira: phycocyanobilin, phycoerythrobilin, phycourobilin, and folic acid. These four compounds showed reliable binding energies comprised between − 6.95 and − 7.45 kcal.mol −1 in Autodock Vina and between − 9.285 and − 10.35 kcal.mol −1 with SwissDock. Toxicity prediction as well as current regulations provided promising arguments for the inclusion of these compounds in further studies to assess their ability to compete with the SARS-CoV-2/ACE2 complex both in vitro and in vivo.

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Not One, But Five: Virtual Screening-Driven Drug Discovery of SARS-CoV2 Enzyme Inhibitors Targeting Viral Attachment, Replication and Post-Translational Infection Mechanisms

Cited by 4 publications

References 19 publications

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

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

Kapang endofit sebagai sumber senyawa aktif antivirus yang menjanjikan: Suatu Kajian Pustaka

Docking and in silico toxicity assessment of Arthrospira compounds as potential antiviral agents against SARS-CoV-2

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