Eveline M. Bezerra

Antipsychotic Haloperidol Binding to the Human Dopamine D3 Receptor: Beyond Docking Through QM/MM Refinement Toward the Design of Improved Schizophrenia Medicines

As the dopamine D3R receptor is a promising target for schizophrenia treatment, an improved understanding of the binding of existing antipsychotics to this receptor is crucial for the development of new potent and more selective therapeutic agents. In this work, we have used X-ray cocrystallization data of the antagonist eticlopride bound to D3R as a template to predict, through docking essays, the placement of the typical antipsychotic drug haloperidol at the D3R receptor binding site. Afterward, classical and quantum mechanics/molecular mechanics (QM/MM) computations were employed to improve the quality of the docking calculations, with the QM part of the simulations being accomplished by using the density functional theory (DFT) formalism. After docking, the calculated QM improved total interaction energy EQMDI = -170.1 kcal/mol was larger (in absolute value) than that obtained with classical molecular mechanics improved (ECLDI = -156.3 kcal/mol) and crude docking (ECRDI = -137.6 kcal/mol) procedures. The QM/MM computations reveal the pivotal role of the Asp110 amino acid residue in the D3R haloperidol binding, followed by Tyr365, Phe345, Ile183, Phe346, Tyr373, and Cys114. Besides, it highlights the relevance of the haloperidol hydroxyl group axial orientation, which interacts with the Tyr365 and Thr369 residues, enhancing its binding to dopamine receptors. Finally, our computations indicate that functional substitutions in the 4-clorophenyl and in the 4-hydroxypiperidin-1-yl fragments (such as C3H and C12H hydrogen replacement by OH or COOH) can lead to haloperidol derivatives with distinct dopamine antagonism profiles. The results of our work are a first step using in silico quantum biochemical design as means to impact the discovery of new medicines to treat schizophrenia.

The quantum biophysics of the isoniazid adduct NADH binding to its InhA reductase target

Mycobacterium tuberculosis (MT) is the aerobic bacterium responsible for the infectious disease tuberculosis (TB). Among the several anti-TB drugs, the first-line anti-TB prodrug isoniazid (INH) has the most potent bactericidal activity. After INH activation by the catalase-peroxidase (KatG) enzyme, the isonicotinic acyl–NADH (INADH) complex is created, which interacts with the enoyl-acyl carrier protein reductase (InhA) active site inhibiting the MT activity. However, mutations in the InhA gene can reduce the InhA–INADH affinity, thus decreasing the large benefits of INH in TB treatment. To provide a deeper understanding of the mechanisms responsible for the anti-TB INADH activity, we study the InhA–INADH interaction using a density functional theory (DFT) quantum mechanical approach. The interaction energies are calculated using the molecular fractionation with the conjugate caps (MFCC) scheme, which allows the quantification of, through the residues’ binding energy, their individual role in the binding pocket, as well as the other relevant residues near the InhA binding site. Besides the importance of amino acid residues with charged lateral chains, our results unveil the role of structural water molecules in the InhA–INADH binding energy. Among all the amino acids in the InhA, we highlight I21 and S94 due to their relevance to the INADH activity after specific InhA mutations. I21 and S94 are strongly bonded to the INADH with an energy of −33.4 kcal mol−1 and −23.1 kcal mol−1, respectively. These values and the positions of I21 and S94 residues relative to the INADH indicate that the ribose of adenine and pyrophosphate groups in INADH strongly influence the total INADH–InhA interaction and consequently the INH anti-TB activity. All reported results contribute to a deeper understanding of the INADH–InhA binding that can be explored in the design of new antitubercular drugs.

Optical Absorption of the Antitrypanocidal Drug Benznidazole in Water

UV-vis optical absorption spectra of the antitrypanocidal drug benznidazole solvated in water were measured for various concentrations. The spectra show a prominent peak around 3.80 eV, while deconvolution of the UV-vis optical absorption spectra revealed six bands centered at 3.60, 3.83, 4.15, 4.99, 5.60, and 5.76 eV. Benznidazole electronic transitions were obtained after density functional theory (DFT) calculations within the polarized continuum (PCM) model for water solvation. Molecular geometry optimizations were carried out, and the measured absorption peaks were related to specific molecular orbital transitions obtained within the time dependent DFT (TD-DFT) with excellent agreement between theory and experiment.

Quantum mechanical ab initio calculations of the Raman scattering from psoralens

Calculations of Raman spectra were performed in the case of four furanocoumarins: psoralen, bergapten, xanthotoxin, and isopimpinellin. The Raman bands were assigned by using the results for wavevectors also obtained through these calculations. It is shown that an easy distinction between the four compounds can be obtained by the analysis of the higher wavenumber region of the spectrum where the stretching modes of atoms pertaining to the radicals appear. The use of the other spectral regions is possible for this task, but at the expense of some additional reasoning.