In silico investigation and potential therapeutic approaches of natural products for COVID-19: Computer-aided drug design perspective

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a substantial number of deaths around the world, making it a serious and pressing public health hazard. Phytochemicals could thus provide a rich source of potent and safer anti-SARS-CoV-2 drugs. The absence of approved treatments or vaccinations continues to be an issue, forcing the creation of new medicines. Computer-aided drug design has helped to speed up the drug research and development process by decreasing costs and time. Natural compounds like terpenoids, alkaloids, polyphenols, and flavonoid derivatives have a perfect impact against viral replication and facilitate future studies in novel drug discovery. This would be more effective if collaboration took place between governments, researchers, clinicians, and traditional medicine practitioners' safe and effective therapeutic research. Through a computational approach, this study aims to contribute to the development of effective treatment methods by examining the mechanisms relating to the binding and subsequent inhibition of SARS-CoV-2 ribonucleic acid (RNA)-dependent RNA polymerase (RdRp). The in silico method has also been employed to determine the most effective drug among the mentioned compound and their aquatic, nonaquatic, and pharmacokinetics' data have been analyzed. The highest binding energy has been reported -11.4 kcal/mol against SARS-CoV-2 main protease (7MBG) in L05. Besides, all the ligands are non-carcinogenic, excluding L04, and have good water solubility and no AMES toxicity. The discovery of preclinical drug candidate molecules and the structural elucidation of pharmacological therapeutic targets have expedited both structure-based and ligand-based drug design. This review article will assist physicians and researchers in realizing the enormous potential of computer-aided drug design in the design and discovery of therapeutic molecules, and hence in the treatment of deadly diseases.

Keywords: COVID-19; SARS-CoV-2; alkaloids; drug design; natural products; virtual screening.

Figure 1

Potential therapeutic strategies are concerned with four aspects: inhibition of virus entry, virus replication, the release of virus offspring, and modifying RAAS. Viral S-protein bonding to ACE2 1. Activity of TMPRSS; 2. Endocytic pathway-Cleavage of S-protein by cathepsin L; 3. Internalization of virus prevented; 4. The replicative activity of RTC inhibited; 5. Increase intracellular Zn²⁺ concentration; 6.Inhibition of viroporin mediated viral budding; 7. Blockage of ACE2 resulting in excessive inflammation; 8. AT1R; 9. 3CL^Pro,3 -chymotrypsin like protease; ACE2; AT1R; S, spike; N, nucleocapsid; E, envelop; M, membrane; PL^Pro, pepsin like protease; PP, polyprotein; RAAS; RTC, replication-transcription complex; TMPRSS2, transmembrane protease serine 2 (Prasansuklab et al., 2020).

Figure 2

Natural derivatives with antiviral activity against SARS-CoV- 1. Ferruginol (A), 8β-hydroxyabiet-9(11),13-dien-12-one (B), 7β-hydroxydeoxycryptojaponol (C), 3β,12-diacetoxyabiet-6,8,11,13-tetraene (D), betunolic acid (E), and savinin (F) (Prasansuklab et al., 2020).

Figure 3

Toxic alkaloids of Veratrum with antiviral activity (Prasansuklab et al., 2020).

Figure 4

Metabolites virtually screened as ACE2 inhibitors of SARS-CoV-2 (da Silva Antonio et al., 2020a).

Figure 5

Natural metabolites are suggested as inhibitors of the 3CL^pro of the SARS-CoV-2 (da Silva Antonio et al., 2020a).

Figure 6

Protein-ligand interaction and their active sides based on High binding energy.