Design, molecular docking, drug-likeness, and molecular dynamics studies of 1,2,4-trioxane derivatives as novel Plasmodium falciparum falcipain-2 (FP-2) inhibitors

Abstract

Despite significant progress made in drug discovery and development over the past few decades, malaria remains a life-threatening infectious disease across the globe. Because of the widespread emergence of drug-resistant strains of Plasmodium falciparum, the clinical utility of existing drug therapies including Artemisinin-based Combination Therapies (ACTs) in the treatment of malaria has been increasingly limited. It has become a serious health concern which, therefore, necessitates the development of novel drug molecules and/or alternative therapies to combat, particularly resistant P. falciparum. The objective of the present study was to develop 1,2,4-trioxane derivatives as novel antimalarial agents that would be effective against resistant P. falciparum. In our study, 15 new trioxane derivatives were designed by molecular modification of the 1,2,4-trioxane scaffold as possible antimalarial agents. Molecular modeling studies of trioxane derivatives were performed based on the CADD approach using Biovia Discovery Studio (DS) 2018 software. The protein-ligand docking study was performed against P. falciparum falcipain 2 (FP-2) using the simulation-based docking protocol LibDock by the flexible docking method.The assessment of drug-likeness, ADMET properties, and toxicity was also performed. Furthermore, the compounds CC3 and CC7, which showed the best binding affinity against the target P. falciparum FP-2, were investigated by molecular dynamics (MD) simulation studies followed by the calculation of MM-PBSA binding free energy of protein-ligand complexes using DS 2020. Results of the docking study showed that among the 15 compounds, three trioxane derivatives were found to possess promising binding affinity with LibDock scores ranging from 117.16 to 116.90. Drug-likeness, ADMET, and toxicity properties were found to be satisfactory for all the compounds. Among the 15 compounds, two compounds, namely CC3 and CC7, showed the highest binding affinity against FP-2 with LibDock score of 117.166 and 117.200, respectively. The Libdock score of the co-crystal inhibitor was 114.474. MD studies along with MM-PBSA calculations of binding energies further confirmed the antimalarial potential of the compounds CC3 and CC7, with the formation of well-defined and stable receptor-ligand interactions against the P. falciparum FP-2 enzyme. Additionally, the selectivity of trioxane hits identified as potential inhibitors of P. falciparum cysteine protease FP-2 was determined on human cysteine proteases such as cathepsins (Cat K and Cat L), which are host homologous. Finally, it was concluded that the newly designed 1,2,4trioxane derivatives can be further studied for in vitro and in vivo antimalarial activities for their possible development as potent antimalarial agents effective against resistant P. falciparum.

Exploring the structural, photophysical and optoelectronic properties of a diaryl heptanoid curcumin derivative and identification as a SARS-CoV-2 inhibitor

“…A ligand that forms as many hydrogen bonds as possible with the active site residues of the target protein molecule is said to produce a well-defined and strong protein-ligand interaction [73] . In MD simulations, measuring the number of hydrogen bonds formed by the ligand with a protein molecule is also an important property for the determination of the strength and stability of the protein-ligand complex [74] . The graphs of RMSD, RMSF, Rg and H bonds numbers of PLpro- C-NMe2 and PLpro-TTT complexes are presented in Figure 12 .…”

“…The topology of the proteins was created with gromos54a7 force field [41] and SCP water model. Topology files of ligand were obtained via the GlycoBioChem PRODRG2 [42] server. Triclinic box type and simple point charge SPC was preferred for solvation at a distance of 10 Å from the protein-ligand complex.…”

A computational study of Di-substituted 1,2,3-triazole derivatives as potential drug candidates against Mycobacterium tuberculosis: 3D-QSAR, molecular docking, molecular dynamics, and ADMETox

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Valorization of Adhatoda vasica leaves: Extraction, in vitro analyses and in silico approaches

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