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Effect of the intramolecular hydrogen bond in the active metabolite analogs of leflunomide for blocking the Plasmodium falciparum dihydroorotate dehydrogenase enzyme: QTAIM, NBO, and docking study.
Curr Comput Aided Drug Des. 2020 May 27 [Online ahead of print]CC

Abstract

Leflunomide (LFM) and its active metabolite, teriflunomide (TFM), have drawn a lot of attention for their anticancer activities, treatment of rheumatoid arthritis and malaria due to their capability to inhibit dihydroorotate dehydrogenase (DHODH) and Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme. In this investigation, the strength of intramolecular hydrogen bond (IHB) in five analogs of TFM (ATFM) has been analyzed employing density functional theory (DFT) using B3LYP/6-311++G (d, p) level and molecular orbital analysis in the gas phase and water solution. A detailed electronic structure study has been performed using the quantum theory of atoms in molecules (QTAIM) and the hydrogen bond energies (EHB) of stable conformer obtained in the range of 76-97 kJ/mol, as a medium hydrogen bond. The effect of substitution on the IHB nature has been studied by natural bond orbital analysis (NBO). 1H NMR calculations show an upward trend in the proton chemical shift of the enolic proton in the chelated ring (14.5 to 15.7ppm) by increasing the IHB strength. All the calculations confirmed the strongest IHB in 5-F-ATFM and the weakest IHB in 2-F-ATFM. Molecular orbital analysis, including the HOMO-LUMO gap and chemical hardness, was performed to compare the reactivity of inhibitors. Finally, molecular docking analysis was carried out to identify the potency of inhibition of these compounds against PfDHODH enzyme.

Authors+Show Affiliations

Department of Chemistry, Faculty of Physics & Chemistry, Alzahra University, Tehran. Iran.Department of Chemistry, Faculty of Physics & Chemistry, Alzahra University, Tehran. Iran.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32459610

Citation

Heidarian, Reihaneh, and Mansoureh Zahedi-Tabrizi. "Effect of the Intramolecular Hydrogen Bond in the Active Metabolite Analogs of Leflunomide for Blocking the Plasmodium Falciparum Dihydroorotate Dehydrogenase Enzyme: QTAIM, NBO, and Docking Study." Current Computer-aided Drug Design, 2020.
Heidarian R, Zahedi-Tabrizi M. Effect of the intramolecular hydrogen bond in the active metabolite analogs of leflunomide for blocking the Plasmodium falciparum dihydroorotate dehydrogenase enzyme: QTAIM, NBO, and docking study. Curr Comput Aided Drug Des. 2020.
Heidarian, R., & Zahedi-Tabrizi, M. (2020). Effect of the intramolecular hydrogen bond in the active metabolite analogs of leflunomide for blocking the Plasmodium falciparum dihydroorotate dehydrogenase enzyme: QTAIM, NBO, and docking study. Current Computer-aided Drug Design. https://doi.org/10.2174/1573409916666200527133126
Heidarian R, Zahedi-Tabrizi M. Effect of the Intramolecular Hydrogen Bond in the Active Metabolite Analogs of Leflunomide for Blocking the Plasmodium Falciparum Dihydroorotate Dehydrogenase Enzyme: QTAIM, NBO, and Docking Study. Curr Comput Aided Drug Des. 2020 May 27; PubMed PMID: 32459610.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of the intramolecular hydrogen bond in the active metabolite analogs of leflunomide for blocking the Plasmodium falciparum dihydroorotate dehydrogenase enzyme: QTAIM, NBO, and docking study. AU - Heidarian,Reihaneh, AU - Zahedi-Tabrizi,Mansoureh, Y1 - 2020/05/27/ PY - 2019/12/13/received PY - 2020/02/17/revised PY - 2020/05/06/accepted PY - 2020/5/28/entrez PY - 2020/5/28/pubmed PY - 2020/5/28/medline KW - DFT KW - Hydrogen bond. KW - Leflunomide KW - NBO KW - PfDHODH KW - Teriflunomide JF - Current computer-aided drug design JO - Curr Comput Aided Drug Des N2 - Leflunomide (LFM) and its active metabolite, teriflunomide (TFM), have drawn a lot of attention for their anticancer activities, treatment of rheumatoid arthritis and malaria due to their capability to inhibit dihydroorotate dehydrogenase (DHODH) and Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme. In this investigation, the strength of intramolecular hydrogen bond (IHB) in five analogs of TFM (ATFM) has been analyzed employing density functional theory (DFT) using B3LYP/6-311++G (d, p) level and molecular orbital analysis in the gas phase and water solution. A detailed electronic structure study has been performed using the quantum theory of atoms in molecules (QTAIM) and the hydrogen bond energies (EHB) of stable conformer obtained in the range of 76-97 kJ/mol, as a medium hydrogen bond. The effect of substitution on the IHB nature has been studied by natural bond orbital analysis (NBO). 1H NMR calculations show an upward trend in the proton chemical shift of the enolic proton in the chelated ring (14.5 to 15.7ppm) by increasing the IHB strength. All the calculations confirmed the strongest IHB in 5-F-ATFM and the weakest IHB in 2-F-ATFM. Molecular orbital analysis, including the HOMO-LUMO gap and chemical hardness, was performed to compare the reactivity of inhibitors. Finally, molecular docking analysis was carried out to identify the potency of inhibition of these compounds against PfDHODH enzyme. SN - 1875-6697 UR - https://www.unboundmedicine.com/medline/citation/32459610/Effect_of_the_intramolecular_hydrogen_bond_in_the_active_metabolite_analogs_of_leflunomide_for_blocking_the_Plasmodium_falciparum_dihydroorotate_dehydrogenase_enzyme:_QTAIM,_NBO,_and_docking_study L2 - http://www.eurekaselect.com/182309/article DB - PRIME DP - Unbound Medicine ER -
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