Alkaloids from Cryptolepis sanguinolenta as Potential Inhibitors of SARS-CoV-2 Viral Proteins: An In Silico Study

Abstract

The ongoing global pandemic caused by the human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions of people and claimed hundreds of thousands of lives. The absence of approved therapeutics to combat this disease threatens the health of all persons on earth and could cause catastrophic damage to society. New drugs are therefore urgently required to bring relief to people everywhere. In addition to repurposing existing drugs, natural products provide an interesting alternative due to their widespread use in all cultures of the world. In this study, alkaloids from Cryptolepis sanguinolenta have been investigated for their ability to inhibit two of the main proteins in SARS-CoV-2, the main protease and the RNA-dependent RNA polymerase, using in silico methods. Molecular docking was used to assess binding potential of the alkaloids to the viral proteins whereas molecular dynamics was used to evaluate stability of the binding event. The results of the study indicate that all 13 alkaloids bind strongly to the main protease and RNA-dependent RNA polymerase with binding energies ranging from -6.7 to -10.6 kcal/mol. In particular, cryptomisrine, cryptospirolepine, cryptoquindoline, and biscryptolepine exhibited very strong inhibitory potential towards both proteins. Results from the molecular dynamics study revealed that a stable protein-ligand complex is formed upon binding. Alkaloids from Cryptolepis sanguinolenta therefore represent a promising class of compounds that could serve as lead compounds in the search for a cure for the corona virus disease.

Figure 1

Structures of Cryptolepis sanguinolenta alkaloids used in this study.

Figure 2

(a) View of 3D interaction of cryptomisirine with M^pro pocket residues (left with black labels) and 2D interactions colored by interaction type (right). (b) View of 3D interaction of cryptospirolepine with M^pro pocket residues (left with black labels) and 2D interactions colored by interaction type explained in legend (right).

Figure 3

(a) View of 3D interaction of cryptomisrine with RdRp pocket residues (left with black labels) and 2D interactions colored by interaction type (right). (b) View of 3D interaction of cryptospirolepine with RdRp pocket residues (left with black labels) and 2D interactions colored by interaction type explained in legend (right).

Figure 4

(a) View of 3D interaction of cryptoquindoline with RdRpol pocket residues (left with black labels) and 2D interactions colored by interaction type (right). (b) View of 3D interaction of cryptomisrine with RdRpol pocket residues (left with black labels) and 2D interactions colored by interaction type explained in legend (right).

Figure 5

Room mean square deviation (RMSD) of cryptomisrine-M^pro (a), cryptomisrine-RdRp (c), and cryptomisrine-RdRpol (e) complexes. Root mean square fluctuation (RMSF) of cryptomisrine-M^pro (b), cryptomisrine-RdRp (d), and cryptomisrine-RdRpol (f) complexes. The secondary structure schematic added to the top and bottom margins of the figure shows helices as black, strands as gray, and loops as white, with larger fluctuations predicted for loop regions.