Computational Design of Thioxanthone Derivatives as Potential Antimalarial Agents through <i>Plasmodium falciparum</i> Protein Inhibition

Abstract

Plasmodium falciparum (P. falciparum) is the most fatal among the other Plasmodium parasites that infect humans with the malaria disease. Currently, the resistance of P. falciparum against some antifolate drugs has become a severe problem. On the other hand, xanthone and thioxanthone derivatives have been reported to have remarkable antimalarial activity. However, molecular docking studies have not evaluated thioxanthone derivative compounds as antimalarial agents. Accordingly, this research investigated the binding pose and inhibition mechanism of several thioxanthone derivatives against P. falciparum proteins DHFR (PDB ID: 1J3K) and DHODH (PDB ID: 1TV5) through molecular docking study. The compound structures were geometrically optimized using Gaussian 09 software and docked to the receptors using AutoDock4 software. The results showed that the free binding energy of thioxanthone derivatives ranged between -6.77 to -7.50 and -8.45 to -9.55 kcal mol–1 against pfDHFR and pfDHODH, respectively, with RMSD values of less than 2 Å. Compound F (4-iodo-3,4-dihydroxy-thioxanthone) gave the most substantial free binding energy against both proteins. Furthermore, the hydrogen bond interaction of compound F was the same as the native ligands of pfDHFR and pfDHODH. These results suggested that compound F has a more robust interaction in pfDHFR and pfDHODH. Thus, it is promising to further evaluate the compound as a candidate for a new antimalarial agent.

In Silico Investigation of Tropical Natural Product for Wild-Type and Quadrupole Mutant PfDHFR Inhibitors as Antimalarial Candidates

“…Hydrophobic interactions with several amino acids, such as Leu46, Met55, and Phe58, strongly supported the stability of the complex between compound C90 and the quadrupole mutant PfDHFR. 27…”

Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective

“…Along the same lines, another study evaluated, using molecular docking, binding poses, the mechanism of inhibition of various thioxanthone derivatives against P. falciparum DHODH and DHFR proteins. Few studies have examined the binding of Pf DHODH.…”

“…Alzain et al 24 identified potential new Pf DHODH inhibitors through computational screening using molecular docking, MM-GBSA calculations, ADME filtering, and molecular dynamics simulations. Along the same lines, another study evaluated, using molecular docking, binding poses, the mechanism of inhibition of various thioxanthone derivatives against P. falciparum DHODH and DHFR 25 proteins. Few studies have examined the binding of Pf DHODH.…”