Anti-HIV reverse transcriptase plant polyphenolic natural products with in silico inhibitory properties on seven non-structural proteins vital in SARS-CoV-2 pathogenesis

Von Novi O de Leon; Joe Anthony H Manzano; Delfin Yñigo H Pilapil 4th; Rey Arturo T Fernandez; James Kyle Anthony R Ching; Mark Tristan J Quimque; Jay Carl M Agbay; Kin Israel R Notarte; Allan Patrick G Macabeo

doi:10.1186/s43141-021-00206-2

Anti-HIV reverse transcriptase plant polyphenolic natural products with in silico inhibitory properties on seven non-structural proteins vital in SARS-CoV-2 pathogenesis

J Genet Eng Biotechnol. 2021 Jul 16;19(1):104. doi: 10.1186/s43141-021-00206-2.

Authors

Von Novi O de Leon^{1

2}, Joe Anthony H Manzano^{1

2}, Delfin Yñigo H Pilapil 4th^{1

2}, Rey Arturo T Fernandez¹, James Kyle Anthony R Ching^{1

3}, Mark Tristan J Quimque^{1

4

5}, Jay Carl M Agbay^{5

6}, Kin Israel R Notarte⁷, Allan Patrick G Macabeo⁸

Affiliations

¹ Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, España Blvd., 1015, Manila, Philippines.
² Department of Biological Sciences, College of Science, University of Santo Tomas, España Blvd., 1015, Manila, Philippines.
³ Department of Chemistry, College of Science, University of Santo Tomas, España Blvd., 1015, Manila, Philippines.
⁴ The Graduate School, University of Santo Tomas, España Blvd., 1015, Manila, Philippines.
⁵ Chemistry Department, College of Science and Mathematics, Mindanao State University - Iligan Institute of Technology, Tibanga, 9200, Iligan City, Philippines.
⁶ Philippine Science High School - Central Mindanao Campus, 9217 Balo-I, Lanao del Norte, Philippines.
⁷ Faculty of Medicine and Surgery, University of Santo Tomas, España Blvd., 1015, Manila, Philippines.
⁸ Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, España Blvd., 1015, Manila, Philippines. agmacabeo@ust.edu.ph.

Abstract

Background: Accessing COVID-19 vaccines is a challenge despite successful clinical trials. This burdens the COVID-19 treatment gap, thereby requiring accelerated discovery of anti-SARS-CoV-2 agents. This study explored the potential of anti-HIV reverse transcriptase (RT) phytochemicals as inhibitors of SARS-CoV-2 non-structural proteins (nsps) by targeting in silico key sites in the structures of SARS-CoV-2 nsps. One hundred four anti-HIV phytochemicals were subjected to molecular docking with nsp3, 5, 10, 12, 13, 15, and 16. Top compounds in complex with the nsps were investigated further through molecular dynamics. The drug-likeness and ADME (absorption, distribution, metabolism, and excretion) properties of the top compounds were also predicted using SwissADME. Their toxicity was likewise determined using OSIRIS Property Explorer.

Results: Among the top-scoring compounds, the polyphenolic functionalized natural products comprised of biflavones 1, 4, 11, 13, 14, 15; ellagitannin 9; and bisisoquinoline alkaloid 19 were multi-targeting and exhibited strongest binding affinities to at least two nsps (binding energy = - 7.7 to - 10.8 kcal/mol). The top ligands were stable in complex with their target nsps as determined by molecular dynamics. Several top-binding compounds were computationally druggable, showed good gastrointestinal absorptive property, and were also predicted to be non-toxic.

Conclusions: Twenty anti-HIV RT phytochemicals showed multi-targeting inhibitory potential against SARS-CoV-2 non-structural proteins 3, 5, 10, 12, 13, 15, and 16. Our results highlight the importance of polyhydroxylated aromatic substructures for effective attachment in the binding/catalytic sites of nsps involved in post-translational mechanism pathways. As such with the nsps playing vital roles in viral pathogenesis, our findings provide inspiration for the design and discovery of novel anti-COVID-19 drug prototypes.

Keywords: ADMET; Alkaloid; HIV reverse transcriptase; Molecular docking; Non-structural proteins; Polyphenolics; SARS-CoV-2; Terpenoids.