Theoretical analysis of the binding of iron(III) protoporphyrin IX to 4-methoxyacetophenone thiosemicarbazone via DFT-D3, MEP, QTAIM, NCI, ELF, and LOL studies

Nyiang Kennet Nkungli; Julius Numbonui Ghogomu

doi:10.1007/s00894-017-3370-4

Theoretical analysis of the binding of iron(III) protoporphyrin IX to 4-methoxyacetophenone thiosemicarbazone via DFT-D3, MEP, QTAIM, NCI, ELF, and LOL studies

J Mol Model. 2017 Jul;23(7):200. doi: 10.1007/s00894-017-3370-4. Epub 2017 Jun 9.

Authors

Nyiang Kennet Nkungli¹, Julius Numbonui Ghogomu²

Affiliations

¹ Laboratory of Noxious Chemistry and Environmental Engineering, Department of Chemistry, Faculty of Science, University of Dschang, P.O. Box 67, Dschang, Cameroon.
² Laboratory of Noxious Chemistry and Environmental Engineering, Department of Chemistry, Faculty of Science, University of Dschang, P.O. Box 67, Dschang, Cameroon. ghogsjuju@hotmail.com.

PMID: 28597191
DOI: 10.1007/s00894-017-3370-4

Abstract

Thiosemicarbazones display diverse pharmacological properties, including antimalarial activities. Their pharmacological activities have been studied in depth, but little of this research has focused on their antimalarial mode of action. To elucidate this antimalarial mechanism, we investigated the nature of the interactions between iron(III) protoporphyrin IX (Fe(III)PPIX) and the thione-thiol tautomers of 4-methoxyacetophenone thiosemicarbazone (MAPTSC). Dispersion-corrected density functional theory (DFT-D3), the quantum theory of atoms in molecules (QTAIM), the noncovalent interaction (NCI) index, the electron localization function (ELF), the localized orbital locator (LOL), and thermodynamic calculations were employed in this work. Fe(III)PPIX-MAPTSC binding is expected to inhibit hemozoin formation, thereby preventing Fe(III)PPIX detoxification in plasmodia. Preliminary studies geared toward the identification of atomic binding sites in the thione-thiol tautomers of MAPTSC were carried out using molecular electrostatic potential (MEP) maps and conceptual DFT-based local reactivity indices. The thionic sulfur and the ² N-azomethine nitrogen/thiol sulfur of, respectively, the thione and thiol tautomers of MAPTSC were identified as the most favorable nucleophilic sites for electrophilic attack. The negative values of the computed Fe(III)PPIX-MAPTSC binding energies, enthalpies, and Gibbs free energies are indicative of the existence and stability of Fe(III)PPIX-MAPTSC complexes. MAPTSC-Fe(III) coordinate bonds and strong hydrogen bonds (N-H···O) between the NH₂ group in MAPTSC and the C=O group in one propionate side chain of Fe(III)PPIX are crucial to Fe(III)PPIX-MAPTSC binding. QTAIM, NCI, ELF, and LOL analyses revealed a subtle interplay of weak noncovalent interactions dominated by dispersive-like van der Waals interactions between Fe(III)PPIX and MAPTSC that stabilize the Fe(III)PPIX-MAPTSC complexes.

Keywords: Antimalarial mechanism; DFT-D3; Fe(III)PPIX–MAPTSC; MEP; NCI index; QTAIM.