Identification of Potential Antimalarial Drug Candidates Targeting Falcipain-2 Protein of Malaria Parasite—A Computational Strategy

Abstract

Falcipain-2 (FP-2) is one of the main haemoglobinase of P. falciparum which is an important molecular target for the treatment of malaria. In this study, we have screened alkaloids to identify potential inhibitors against FP-2 since alkaloids possess great potential as anti-malarial agents. A total of 340 alkaloids were considered for the study using a series of computational pipelines. Initially, pharmacokinetics and toxicity risk assessment parameters were applied to screen compounds. Subsequently, molecular docking algorithms were utilised to understand the binding efficiency of alkaloids against FP-2. Further, oral toxicity prediction was done using the pkCSM tool, and 3D pharmacophore features were analysed using the PharmaGist server. Finally, MD simulation was performed for Artemisinin and the top 3 drug candidates (Noscapine, Reticuline, Aclidinium) based on docking scores to understand the functional impact of the complexes, followed by a binding site interaction residues study. Overall analysis suggests that Noscapine conceded good pharmacokinetics and oral bioavailability properties. Also, it showed better binding efficiency with FP-2 when compared to Artemisinin. Interestingly, structure alignment analysis with artemisinin revealed that Noscapine, Reticuline, and Aclidinium might possess similar biological action. Molecular dynamics and free energy calculations revealed that Noscapine could be a potent antimalarial agent targeting FP-2 that can be used for the treatment of malaria and need to be studied experimentally in the future.

Potential antiviral activity of eleutherine, isoeleutherine, eleuthinone and elecanacine compounds in Eleutherine palmifolia (L.) Merr against NSP3 SARS-COV-2: In silico study

“…To assess the mutagenicity of compounds, prediction of AMES toxicity was performed in this research. Hepatotoxicity testing was performed to determine a compounds hepatotoxicity, a compound was considered hepatotoxic if it interfered with the normal physiological function of the liver [26]. Furthermore, skin sensitization was performed to identify compounds that could cause an allergic reaction on the skin.…”

Investigation on Anti‐plasmodial Agents Against wild‐type PfDHFR Through In Silico Computational Tools

“…The figures 6d and 6e presented the plots of solvent assessable surface area (SASA) and HB, respectively within a suitable range of 490-538 nm 2 for ligand-Figure 5. BOILED egg model of hit compounds (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). BBB and GI permeability have been indicated by the yellow and colorless zones, respectively.…”

“…The Biovia Discovery Studio 2021 was utilized to visualize and analyze docking interactions between proteins and ligands. [41] The 2-D structures of compounds (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) are provided in the supplementary material (Figures S1-S3).…”

“…Various physiochemical features of hits (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) and pyrimethamine (1) were investigated using Swiss ADME [44] and pkCSM, [46,45] including MW, number of HBD, number of HBA, Log P, and number of RB. Several criteria, including Ghose's rule, Lipinski's rule of 5, Veber's rule, Muegge's rule, and Egan's rule have been applied to the hits to check drug likeliness.…”

In vitro and in vivo evaluation of Noscapine as a potential antimalarial vis-à-vis standard Dihydroartemisinin (DHA) against Plasmodium falciparum 3D7, P. falciparum clinical isolate Pf140/SS and P. berghei ANKA

“…Based on the study ndings and the differences in the morphological changes in parasites before and after Noscapine treatment (Fig 2 ), we could hypothesize the probable mechanism of action for Noscapine to act on the parasitized RBCs. In silico studies have recently demonstrated that in comparison to DHA, Noscapine could have better binding e cacy with the Falcipain-2(FP-2) protein, and therefore has the potential for blocking hemoglobin hydrolysis and parasite development (Nema et al 2022). Falcipain-2(FP-2) is the papain-like cysteine protease of P. falciparum localised in the food vacuole, and responsible for cleaving the membrane skeletal proteins during late parasite development.…”