An In Silico Study of the Interactions of Alkaloids from Cryptolepis sanguinolenta with Plasmodium falciparum Dihydrofolate Reductase and Dihydroorotate Dehydrogenase

Abstract

The Plasmodium falciparum dihydrofolate reductase (PfDHFR) and dihydroorotate dehydrogenase (PfDHODH) are essential for Plasmodium falciparum growth and development, and have been validated as targets for the development of new antimalarial agents. Several alkaloids isolated from Cryptolepis sanguinolenta have been reported to have antiplasmodial activity, but their protein targets are unknown. Therefore, molecular docking and molecular dynamics simulations were used to investigate the interactions and stability of the alkaloids with PfDHFR and PfDHODH. Based on physicochemical characteristics, alkaloids were grouped as sterically bulky (sb) or planar (pg). Docking results revealed strong binding affinities (−6.0 to −13.4 kcal/mol) of the alkaloids against PfDHODH and various strains of PfDHFR while interacting with key residues such as Asp54 and Phe58 in PfDHFR. The pg alkaloids had high binding affinity and preference for the inhibitor binding domain over the flavin mononucleotide (FMN) binding domain in PfDHODH due to size considerations. From the molecular dynamics trajectories, protein-alkaloid complexes were stable throughout the simulation, with supporting evidence from root mean square deviations, root mean square fluctuations, radius of gyration, free binding energies, and other parameters. We report herein that biscryptolepine and cryptomisrine (sb class), as well as cryptolepinone, cryptoheptine, cryptolepine, and neocryptolepine (pg class), are capable of inhibiting PfDHFR effectively in pyrimethamine sensitive and resistant cells. Also, our results show that alkaloids of the pg class can inhibit PfDHODH as FMN decoys, as well as direct enzyme inhibitors, thereby halting crucial protein function.

Alkaloidal Extracts from Avicennia africana P. Beauv. (Avicenniaceae) Leaf: An Antiplasmodial, Antioxidant, and Erythrocyte Viable

“…Our findings are consistent with those of Erhunse et al regarding the antimalarial effect of isoquinoline alkaloids such as berberine and palmatine [ 42 ]. Kyei et al also demonstrated the potential antimalarial activity of cryptolepine and isocryptolepine [ 43 ]. The display of the potent antiplasmodial activity of the alkaloidal extracts in the present study confirmed earlier reports regarding the diversity of bioactive metabolites and, importantly, the antiplasmodial properties of several classes of alkaloids, such as the indole and isoquinoline classes [ 13 , 44 , 45 ].…”

N-Substituted Phenylhydrazones Kill the Ring Stage of Plasmodium falciparum

“…Each docking experiment was repeated in four technical runs to ensure reproducibility, and in each run, nine poses were generated and ranked according to their binding energies by AutoDock Vina [ 13 ]. Selection of the best poses was based on ligands' binding energy and the ability of the ligands to form optimal interactions with active site residues of the target proteins [ 13 ]. The root mean square deviation of the redocked ligand was calculated in PyMOL.…”

“…Prior to this step, Charmm36-july2022 force field for GROMACS was downloaded via Mackerel lab online server. Since GROMACS does not have an internal module for ligand topology file preparation, we relied on CHARMM general force field online server as an external tool to generate the ligand topology file [ 13 , 14 ]. A complex file was then generated by merging the topology file of the ligand and the protein.…”

Computational Studies Provide a Molecular Basis for the Quorum Sensing Inhibitory Action of Compounds from Dioon spinulosum Dyer Ex Eichler

“…The validity was confirmed by the low RMSD (< 2 Å) of the redocked ligand from the orientation of the cocrystallized ligand and the replication of observed interactions from the pdb structure. [32] Discovery Studio 2017 R2 client (Dassault Systèmes BIOVIA, (Discovery Studio Visualizer), (2017 R2 Client), San Diego: Dassault Systèmes, ( 2017)) was used to analyze protein-ligand interactions.…”