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.

Current Updates on Naturally Occurring Compounds Recognizing SARS-CoV-2 Druggable Targets

“…Overall, all these alkaloids were able to recognize the active site of the two studied targets. Among these, for SARS-CoV-2 Mpro, cryptospirolepine well interacted with the catalytic dyad; for the polymerase, the best one was the cryptomisrine which was involved in π -cation interactions with Arg553 and Arg624 residues of SARS-CoV-2 RdRp [ 110 ]. Gyebi et al studied the involvement of these alkaloids in the prevention of SARS-CoV-2 cell entry.…”

Natural and Nature-Derived Products Targeting Human Coronaviruses

“…Regarding 3CL pro , recent efforts, have identified potential inhibitors among: alkaloids [ 133 , 134 , 135 , 136 , 137 , 138 ], and especially indole alkaloids [ 139 , 140 , 141 , 142 , 143 , 144 ]; terpenoids [ 138 ], and especially diterpenes [ 133 , 145 ]; sesquiterpenes [ 134 , 146 , 147 ], sesquiterpene lactones [ 148 ], and triterpenes [ 133 , 136 , 140 , 149 ]; anthocyanins [ 150 , 151 ] and proanthocyanidins [ 152 , 153 ]; ellagitannins [ 153 , 154 ]; flavonoids [ 133 , 137 , 140 , 144 , 147 , 148 , 152 , 155 , 156 , 157 , 158 , 159 , 160 , 161 ], biflavonoids [ 162 ], and macrocyclic flavonoids [ 148 ]; isoflavones [ 144 , 148 ]; chalcones […”

“…The active site of RdRp has been also investigated as a possible target of inhibition finding multiple possible ligands, such as flavonoids, xanthones [ 133 ], polyketides [ 138 ], terpenes and sesquiterpene lactones [ 133 , 138 ], and alkaloids [ 138 , 143 ]. Finally, alkaloids, polyketides and terpenes have shown affinity for non-structural protein 15 (nsp15) of SARS-CoV-2 [ 138 ], while several NPs have been investigated as potential ligands to virulence factors Nsp1 (suppresses type-I IFN expression), Nsp3c (promotes replication of the viral genome and transcription of viral mRNA) and ORF7a (inhibits virus restriction) [ 133 ].…”

Structure-based virtual screening suggests inhibitors of 3-Chymotrypsin-Like Protease of SARS-CoV-2 from Vernonia amygdalina and Occinum gratissimum

“…Structure-based virtual screening (SBVS) has been widely employed to search chemical compound libraries towards bioprospecting novel bioactive molecules against viral drug targets in the on-going campaign against coronavirus pandemic [25,26]. It is a fast, environmentally sound, and cost effective approach used in early-stage of drug discovery process [27].…”