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Unveiling the Molecular Structure of Antimalarial Drugs Chloroquine and Hydroxychloroquine in Solution through Analysis of 1H NMR Chemical Shifts.
Hernandes, Isabel S; Da Silva, Haroldo C; Dos Santos, Hélio F; De Almeida, Wagner B.
  • Hernandes IS; Laboratório de Química Computacional e Modelagem Molecular (LQC-MM), Departamento de Química Inorgânica, Instituto de Química, Universidade Federal Fluminense (UFF), Outeiro de São João Batista s/n, Campus do Valonguinho, Centro, Niterói 24020-141, Rio de Janeiro, Brazil.
  • Da Silva HC; Laboratório de Química Computacional e Modelagem Molecular (LQC-MM), Departamento de Química Inorgânica, Instituto de Química, Universidade Federal Fluminense (UFF), Outeiro de São João Batista s/n, Campus do Valonguinho, Centro, Niterói 24020-141, Rio de Janeiro, Brazil.
  • Dos Santos HF; Núcleo de Estudos em Química Computacional (NEQC), Departamento de Química, ICE, Universidade Federal de Juiz de Fora (UFJF), Campus Universitário, Martelos, Juiz de Fora 36036-330, Minas Gerais, Brazil.
  • De Almeida WB; Laboratório de Química Computacional e Modelagem Molecular (LQC-MM), Departamento de Química Inorgânica, Instituto de Química, Universidade Federal Fluminense (UFF), Outeiro de São João Batista s/n, Campus do Valonguinho, Centro, Niterói 24020-141, Rio de Janeiro, Brazil.
J Phys Chem B ; 125(13): 3321-3342, 2021 04 08.
Article in English | MEDLINE | ID: covidwho-1147824
ABSTRACT
Chloroquine (CQ) and hydroxychloroquine (HCQ) have been standard antimalarial drugs since the early 1950s, and very recently, the possibility of their use for the treatment of COVID-19 patients has been considered. To understand the drug mode of action at the submicroscopic level (atoms and molecules), molecular modeling studies with the aid of computational chemistry methods have been of great help. A fundamental step in such theoretical investigations is the knowledge of the predominant drug molecular structure in solution, which is the real environment for the interaction with biological targets. Our strategy to access this valuable information is to perform density functional theory (DFT) calculations of 1H NMR chemical shifts for several plausible molecular conformers and then find the best match with experimental NMR profile in solution (since it is extremely sensitive to conformational changes). Through this procedure, after optimizing 30 trial distinct molecular structures (ωB97x-D/6-31G(d,p)-PCM level of calculation), which may be considered representative conformations, we concluded that the global minimum (named M24), stabilized by an intramolecular N-H hydrogen bond, is not likely to be observed in water, chloroform, and dimethyl sulfoxide (DMSO) solution. Among fully optimized conformations (named M1 to M30, and MD1 and MD2), we found M12 (having no intramolecular H-bond) as the most probable structure of CQ and HCQ in water solution, which is a good approximate starting geometry in drug-receptor interaction simulations. On the other hand, the preferred CQ and HCQ structure in chloroform (and CQ in DMSO-d6) solution was assigned as M8, showing the solvent effects on conformational preferences. We believe that the analysis of 1H NMR data in solution can establish the connection between the macro level (experimental) and the sub-micro level (theoretical), which is not so apparent to us and appears to be more appropriate than the thermodynamic stability criterion in conformational analysis studies.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Chloroquine / Hydroxychloroquine Type of study: Randomized controlled trials Language: English Journal: J Phys Chem B Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jpcb.1c00609

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Chloroquine / Hydroxychloroquine Type of study: Randomized controlled trials Language: English Journal: J Phys Chem B Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jpcb.1c00609