In Silico and In Vitro Potential of FDA-Approved Drugs for Antimalarial Drug Repurposing against Plasmodium Serine Hydroxymethyltransferases

Malaria has spread in many countries, with a 12% increase in deaths after the coronavirus disease 2019 pandemic. Malaria is one of the most concerning diseases in the Greater Mekong subregion, showing increased drug-resistant rates. Serine hydroxymethyltransferase (SHMT), a key enzyme in the deoxythymidylate synthesis pathway, has been identified as a promising antimalarial drug target due to its conserved folate binding pocket. This study used a molecular docking approach to screen 2509 US Food and Drug Administration (FDA)-approved drugs against seven Plasmodium SHMT structures. Eight compounds had significantly lower binding energies than the known SHMT inhibitors pyrazolopyran(+)-86, tetrahydrofolate, and antimalarial drugs, ranging from 4 to 10 kcal/ mol. Inhibition assays testing the eight compounds against Plasmodium falciparum SHMT (PfSHMT) showed that amphotericin B was a competitive inhibitor of PfSHMT with a half-maximal inhibitory concentration (IC50) of 106 +/- 1 mu M. Therefore, a 500 ns molecular dynamics simulation of Pf SHMT/PLS/amphotericin B was performed. The backbone root-mean-square deviation of the protein-ligand complex indicated the high complex stability during simulations, supported by its radius of gyration, hydrogen-bond interactions, and number of atom contacts. The appreciable binding affinity of amphotericin B for PfSHMT was indicated by their solvated interaction energy (-11.15 +/- 0.09 kcal/mol) and supported by strong ligand-protein interactions (>= 80% occurrences) with its essential residues (i.e., Y78, K151, N262, F266, and V365) predicted by pharmacophore modeling and per-residue decomposition free energy methods. Therefore, our findings identify a promising new PfSHMT inhibitor, albeit with less inhibitory activity, and suggest a core structure that differs from that of previous SHMT inhibitors, thus being a rational approach for novel antimalarial drug design.

Automated summary

This study used molecular docking to screen FDA-approved drugs and identified a new potential inhibitor of Plasmodium falciparum serine hydroxymethyltransferase (PfSHMT). Inhibition assays and molecular dynamics simulations confirmed the inhibitory effect and binding affinity of the compound, suggesting it as a rational approach for novel antimalarial drug design.