Page 122 - ITPS-7-1

INNOSC Theranostics and
Pharmacological Sciences Repurposed Drugs as inhibitors of Pfmrk

Lys26, Tyr96, and Lys100) within the residues of our certain regions of Africa, where both children and
binding site. This is in contrast to our docking result, pregnant women are primarily affected. The spread of this
which indicated the formation of two H-bonds with Lys deadly disease is influenced by local hygiene and overall
26 and Glu18. environmental conditions. Organizations like the WHO
and other leading research institutions continuously strive
3.5. Secondary structure analysis to improve living conditions and bolster our ability to

The comparative analysis of Dictionary of Protein combat this disease [23-25] . There are two most important
Secondary Structure (DSSP) secondary structures for both strategies for controlling this condition: vector control,
Pfmrk and the ligands was calculated using molecular which is highly dependent on our living environment, and
dynamics simulation and is summarized in Table S3. The the development of medicine or vaccines. Although the
secondary structure analysis of Pfmrk reveals similar first vaccine developed for malaria, RTS, S, shows promise,
content in terms of β-sheet, β-bridge, bend, turn, α-helix, its impact on transmission remains limited, which, in turn,
5-helix, and 3-helix when compared to the ligands. In does not significantly affect endemicity [26,27] . The most
addition, Alvesco and Donovex exhibit a broader range of pressing challenge in managing cases of malaria is the
secondary structures, encompassing coil, β-sheet, β-bridge, increasing resistance to the current panel of drugs. Drug
and bend. This observation suggests that these ligands have resistance and cross-resistance among drug combinations
maximum non-covalent interactions with Pfmrk. Orap are prompting the scientific community to explore
demonstrates a more significant turn content, signifying alternatives beyond the current array of medications. The
[23]
its contribution to enhancing protein compactness relative review by Pandey et al. provides an updated account .
to the other ligands. As a result, there is an urgent need to identify alternatives,
particularly in the most affected regions, including several
3.6. MM-PBSA free energy analysis third-world countries. Therefore, a drug repurposing
The total free binding energy for Donovex was determined strategy could be an effective means to screen drugs and
to be −92.87 ± 17.87 kJ/mol, while Lurasidone exhibited a expedite the drug development process.
slightly higher value of −105.9 ± 57.72 kJ/mol. These energy This in silico study aims to identify the potential
values were notably higher than those of the other ligands, FDA-approved drugs that could target the Pfmrk protein
as indicated in Table 3. Donovex and Lurasidone emerged kinase. Through the utilization of molecular docking
as the primary contributors to van der Waals forces, and subsequent molecular dynamics simulations, we
underscoring the significance of hydrophobic interactions focused on gaining insight into the binding interactions
in our protein-ligand interactions. In addition, these two between these screened drugs and Pfmrk’s ATP binding
ligands were observed to exert a notable influence on site. Our approach particularly focused on the unique
promoting a more folded state of Pfmrk. Their strong characteristics of the active site, marked by the presence
binding affinity was evident through their ability to bind of critical residues such as Leu16, Met75, Met91, Ile93,
to the protein’s active site and other binding regions with and Phe143. Our findings highlighted the critical role
relatively higher binding affinity, as reflected in their of H-bonds, hydrophobic interactions, and other non-
considerably low binding energy values. covalent interactions in establishing robust ligand-protein
binding.
4. Discussion
Given Pfmrk’s dual function in both P. falciparum
Malaria remains one of the most dreaded public health cellular replication and its overall life cycle, targeting ATP
concerns, exerting a significant global impact. One of binding has emerged as a potential strategy to inhibit its
the world’s most affected regions by malaria includes kinase activity. Through rigorous analysis, we identified
Table 3. Comprehensive comparative analysis of energetic components in protein‑drug complexes formed post‑simulation

Ligands van der Waal Electrostatic Energy of SASA energy Binding energy
energy (kJ/mol) energy (kJ/mol) solvation (kJ/mol) (kJ/mol) (kJ/mol)
Alvesco −121.789±69.283 −1.518±7.973 65.713±46.072 −13.350±7.725 −70.944±54.776
Donovex −126.353±20.061 −2.796±2.679 51.327±15.995 −15.054±2.503 −92.877±17.872
Lurasidone −127.589±64.217 −7.726±7.060 40.816±23.777 −11.408±5.727 −105.907±57.728
Orap −103.655±100.467 −3.910±6.977 42.897±56.765 −9.701±9.853 −74.369±75.259
Vorapaxar −5.003±28.557 −0.642±4.782 16.218±40.884 −0.269±4.157 10.304±41.271
Abbreviation: SASA: Solvent-accessible surface area.

Volume 7 Issue 1 (2024) 7 https://doi.org/10.36922/itps.1313