Virtual screening of lead compounds for SARS-CoV-2 | Journal of Pharmacy & Pharmacognosy Research

J Pharm Pharmacogn Res 9(5): 730-745, 2021.

Original article

Natural products repurposing of the H5N1-based lead compounds for the most fit inhibitors against 3C-like protease of SARS-CoV-2

[Reutilización de productos naturales de compuestos principales basados en H5N1 para los inhibidores más adecuados contra la proteasa similar a 3C del SARS-CoV-2]

Arli Aditya Parikesit^*, Rizky Nurdiansyah

Department of Bioinformatics, School of Life Sciences, Indonesia International Institute for Life Sciences, Jl. Pulomas Barat Kav. 88 Jakarta 13210 Indonesia.

*E-mail: arli.parikesit@i3l.ac.id

Abstract

Context: COVID-19 pandemic has caused more than 2.7 million mortality worldwide. Although the COVID-19 vaccine has been developed, the amount is still limited, and very few countries have reached ‘herd immunity’ level. In this regard, imported and community infections is still happening in the world. In order to complement the vaccine rollout, the drug is still necessary. Up to now, all the COVID-19 drugs in the market are still in emergency use, and their clinical application is still under tight surveillance. Thus, a breakthrough in drug development is necessary. Based on an extensive protein crystallography experiment, it is known that the 3C-like protease of SARS-CoV-2 plays an important role in the pathogenicity of the virus. Several inhibitors have been developed for this protein, including remdesivir that served as the standard in this experiment. However, recent findings in the wet lab also showed possible significant bioactivities for the repurposed influenza, and human rhinovirus leads for SARS-CoV-2. Previous research has developed flavonoid-based leads as H5N1 virus inhibitors.

Aims: To develop lead compounds to inhibit 3C-like protease of SARS-CoV-2 from the existing H5N1 leads.

Methods: The ligands and protein were prepared with energy minimization and the “add protonation” procedure. Then, the QSAR analysis was conducted to determine whether the ligands fit as leads for the 3C-like protease SARS-CoV-2 inhibitor. Molecular docking simulation was deployed for the selected ligand toward the 3C-like protease enzyme. Moreover, the molecular dynamics simulation was devised to examine the protein flexibility of the protease ligands.

Results: It was found that only 9 out of the 19 repurposed H5N1-leads elicited significant QSAR-based properties for general antivirus, influenza antivirus, and antihuman rhinovirus bioactivities. In this regard, the leads were screened further with molecular docking, in silico ADME-TOX prediction, and molecular dynamics methods. Based on the further screen, the ligands of M00009235 and M00006834 were selected as lead compounds for 3C-like protease SARS-CoV-2 inhibitors.

Conclusions: The ligands of M00009235 and M00006834 were selected as the best leads for inhibiting 3C-like protease of SARS-CoV-2 based on the virtual screening methods.

Keywords: 3C-like protease; COVID-19; molecular docking; molecular dynamics; SARS-CoV-2.

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Resumen

Contexto: La pandemia de COVID-19 ha causado más de 2,7 millones de muertes en todo el mundo. Hasta ahora, todos los medicamentos COVID-19 en el mercado todavía se encuentran en uso de emergencia y su aplicación clínica aún está bajo estricta vigilancia. Por tanto, es necesario un gran avance en el desarrollo de fármacos. Basado en un extenso experimento de cristalografía de proteínas, se sabe que la proteasa de tipo 3C del SARS-CoV-2 juega un papel importante en la patogenicidad del virus. Se han desarrollado varios inhibidores para esta proteína, incluido el remdesivir que sirvió como estándar en este experimento. Sin embargo, hallazgos recientes en el laboratorio también mostraron posibles bioactividades significativas para la influenza reutilizada y los rinovirus humanos para el SARS-CoV-2. Una investigación anterior ha desarrollado líderes basados en flavonoides como inhibidores del virus H5N1.

Objetivos: Desarrollar compuestos líderes para inhibir la proteasa similar a 3C del SARS-CoV-2 de los cables H5N1 existentes.

Métodos: Los ligandos y la proteína se prepararon con el procedimiento de minimización de energía y “agregar protonación”. Luego, se llevó a cabo el análisis QSAR para determinar si los ligandos encajaban como conductores para el inhibidor de la proteasa de tipo 3C SARS-CoV-2. Se implementó la simulación de acoplamiento molecular para el ligando seleccionado hacia la enzima proteasa similar a 3C. Además, la simulación de dinámica molecular se diseñó para examinar la flexibilidad proteica de los ligandos de proteasa.

Resultados: Se encontró que solo 9 de los 19 líderes H5N1 reutilizados obtuvieron propiedades significativas basadas en QSAR para las bioactividades antivirus generales, antivirus contra la influenza y contra rinovirus humanos. En este sentido, los líderes se analizaron más con métodos de acoplamiento molecular, predicción in silico ADME-TOX y dinámica molecular. Basándose en el cribado adicional, se seleccionaron los ligandos de M00009235 y M00006834 como compuestos principales para los inhibidores de proteasa de tipo 3C SARS-CoV-2.

Conclusiones: Los ligandos de M00009235 y M00006834 se seleccionaron como los mejores conductores para inhibir la proteasa de tipo 3C del SARS-CoV-2 basándose en los métodos de cribado virtual.

Palabras Clave: proteasa de tipo 3C; COVID-19; acoplamiento molecular; dinámica molecular; SARS-CoV-2.

Citation Format: Parikesit AA, Nurdiansyah R (2021) Natural products repurposing of the H5N1-based lead compounds for the most fit inhibitors against 3C-like protease of SARS-CoV-2. J Pharm Pharmacogn Res 9(5): 730–745.