RESUMEN
Although many natural product-derived compounds possess anti-leishmanial activities in vitro and in vivo, their molecular targets in the Leishmania parasite remain elusive. This is a major challenge in optimizing these compounds into leads. The Leishmania pteridine reductase (PTR1) is peculiar for folate and pterin metabolism and has been validated as a drug target. In this study, 17 compounds with anti-leishmanial activities were screened against Leishmania major PTR1 (LmPTR1) using molecular docking and molecular dynamics (MD) simulations. All ligands were bound in the active site pocket of LmPTR1 with binding affinities ranging from -11.2 to -5.2 kcal/mol. Agnuside, betulin, betulinic acid, gerberinol, ismailin, oleanolic acid, pristimerin, and ursolic acid demonstrated binding affinities similar to a known inhibitor, methyl 1-(4-{[2,4-diaminopteridin-6-yl) methyl] amino} benzoyl) piperidine-4-carboxylate (DVP). MD simulations revealed that betulin, betulinic acid, ismailin, oleanolic acid, pristimerin, and ursolic acid formed stable complexes with LmPTR1. The binding free energies of the complexes were very good (-87 to -148 kJ/mol), and much higher than the complex of the standard DVP inhibitor and LmPTR1 (-27 kJ/mol). Betulin, betulinic acid, ismailin, oleanolic acid, pristimerin, and ursolic acid likely exert their antileishmanial action by inhibiting PTR1 and could thus be used as a basis for the development of potential antileishmanial chemotherapeutic agents. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00247-8.
RESUMEN
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.