A quantum biochemistry investigation of willardiine partial agonism in AMPA receptors.

We employ quantum biochemistry methods based on the Density Functional Theory (DFT) approach to unveil the detailed binding energy features of willardiines co-crystallized with the AMPA receptor. Our computational results demonstrate that the total binding energies of fluorine-willardiine (FW), hydrogen-willardiine (HW), bromine-willardiine (BrW) and iodine-willardiine (IW) to the iGluR2 ligand-pocket correlate with the agonist binding energies, whose experimental sequential data match our computational counterpart, excluding the HW case. We find that the main contributions to the total willardiine-iGluR2 binding energy are due to the amino acid residues in decreasing order Glu705 > Arg485 > Ser654 > Tyr450 > T655. Furthermore, Met708, which is positioned close to the 5-substituent, attracts HW and FW, but repels BrW and IW. Our results contribute significantly to an improved understanding of the willardiine-iGluR2 binding mechanisms.

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.

Alzheimer's Disease Immunotherapy and Mimetic Peptide Design for Drug Development: Mutation Screening, Molecular Dynamics, and a Quantum Biochemistry Approach Focusing on Aducanumab::Aß2-7 Binding Affinity.

Seven treatments are approved for Alzheimer's disease, but five of them only relieve symptoms and do not alter the course of the disease. Aducanumab (Adu) and lecanemab are novel disease-modifying antiamyloid-ß (Aß) human monoclonal antibodies that specifically target the pathophysiology of Alzheimer's disease (AD) and were recently approved for its treatment. However, their administration is associated with serious side effects, and their use is limited to early stages of the disease. Therefore, drug discovery remains of great importance in AD research. To gain new insights into the development of novel drugs for Alzheimer's disease, a combination of techniques was employed, including mutation screening, molecular dynamics, and quantum biochemistry. These were used to outline the interfacial interactions of the Aducanumab::Aß2-7 complex. Our analysis identified critical stabilizing contacts, revealing up to 40% variation in the affinity of the Adu chains for Aß2-7 depending on the conformation outlined. Remarkably, two complementarity determining regions (CDRs) of the Adu heavy chain (HCDR3 and HCDR2) and one CDR of the Adu light chain (LCDR3) accounted for approximately 77% of the affinity of Adu for Aß2-7, confirming their critical role in epitope recognition. A single mutation, originally reported to have the potential to increase the affinity of Adu for Aß2-7, was shown to decrease its structural stability without increasing the overall binding affinity. Mimetic peptides that have the potential to inhibit Aß aggregation were designed by using computational outcomes. Our results support the use of these peptides as promising drugs with great potential as inhibitors of Aß aggregation.

In silico description of the adsorption of cell signaling pathway proteins ovalbumin, glutathione, LC3, TLR4, ASC PYCARD, PI3K and NF-Kß on 7.0 nm gold nanoparticles: obtaining their Lennard-Jones-like potentials through docking and molecular mechanics.

The impact of vaccination on the world's population is difficult to calculate. For developing different types of vaccines, adjuvants are substances added to vaccines to increase the magnitude and durability of the immune response and the effectiveness of the vaccine. This work explores the potential use of spherical gold nanoparticles (AuNPs) as adjuvants. Thus, we employed docking techniques and molecular mechanics to describe how a AuNP 7.0 nm in diameter interacts with cell signaling pathway proteins. Initially, we used X-ray crystallization data of the proteins ovalbumin, glutathione, LC3, TLR4, ASC PYCARD, PI3K, and NF-Kß to study the adsorption with an AuNP through molecular docking. Therefore, interaction energies were obtained for the AuNP complexes and individual proteins, as well as the AuNP and OVA complex (AuNP@OVA) with each cellular protein, respectively. Results showed that AuNPs had the highest affinity for OVA individually, followed by glutathione, ASC PYCARD domain, LC3, PI3K, NF-Kß, and TLR4. Furthermore, when evaluating the AuNP@OVA complex, glutathione showed a greater affinity with more potent interaction energy when compared to the other studied systems.

Explaining statin inhibition effectiveness of HMG-CoA reductase by quantum biochemistry computations.

By taking advantage of the crystallographic data of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) complexed with statins, a quantum biochemistry study based on the density functional theory is performed to estimate the interaction energy for each statin when one considers binding pockets of different sizes. Assuming a correlation between statin potency and the strength of the total HMGR-statin binding energy, clinical data as well as IC(50) values of these cholesterol-lowering drugs are successfully explained only after stabilization of the calculated total binding energy for a larger size of the ligand-interacting HGMR region, one with a radius of at least 12.0 Å. Actually, the binding pocket radius suggested by classic works, which was based solely on the interpretation of crystallographic data of the HMGR-statin complex, is smaller than that necessary to achieve total binding energy convergence in our simulations. Atorvastatin and rosuvastatin are shown to be the most strongly bound HMGR inhibitors, while simvastatin and fluvastatin are the weakest ones. A binding site, interaction energy between residues and statin atoms, and residues domain (BIRD) panel is constructed, indicating clear quantum biochemistry-based routes for the development of new statin derivatives.

Losartan as an ACE inhibitor: a description of the mechanism of action through quantum biochemistry.

Losartan (LST) is a potent and selective angiotensin II (Ang II) type 1 (AT1) receptor antagonist widely used in the treatment of hypertension. The formation of Ang II is catalyzed by the angiotensin I-converting enzyme (ACE) through proteolytic cleavage of angiotensin I (Ang I), which is involved in the control of blood pressure. Despite the vast literature on the relationship of losartan with the renin-angiotensin system (RAS), the actions of losartan on the sACE enzyme are so far poorly understood. In view of this, we investigated how losartan can interact with the sACE enzyme to block its activity and intracellular signaling. After performing docking assays following quantum biochemistry calculations using losartan and sACE crystallographic data, we report that their interaction results reveal a new mechanism of action with important implications for understanding its effects on hypertension.

Antitumor Potential of the Isoflavonoids (+)- and (-)-2,3,9-Trimethoxypterocarpan: Mechanism-of-Action Studies.

Synthetically derived samples of (+)-(6aS,11aS)-2,3,9-trimethoxypterocarpan [(+)-1] and its enantiomer [(-)-1], both of which are examples of naturally occurring isoflavonoids, were evaluated, together with the corresponding racemate, as cytotoxic agents against the HL-60, HCT-116, OVCAR-8, and SF-295 tumor cell lines. As a result it was established that compound (+)-1 was particularly active with OVCAR-8 cells being the most sensitive and responding in a dose-dependent manner. A study of cell viability and drug-induced morphological changes revealed the compound causes cell death through a mechanism characteristic of apoptosis. Finally, a computational study of the interactions of compound (+)-1 and (S)-monastrol, an established, synthetically derived, potent, and cell-permeant inhibitor of mitosis, with the kinesin-type protein Eg5 revealed that both bind to this receptor in a similar manner. Significantly, compound (+)-1 binds with greater affinity, an effect attributed to the presence of the associated methoxy groups.

Two Binding Geometries for Risperidone in Dopamine D3 Receptors: Insights on the Fast-Off Mechanism through Docking, Quantum Biochemistry, and Molecular Dynamics Simulations.

Risperidone is an atypical antipsychotic used in the treatment of schizophrenia and of symptoms of irritability associated with autism spectrum disorder (ASD). Its main action mechanism is the blockade of D2-like receptors acting over positive and negative symptoms of schizophrenia with small risk of extrapyramidal symptoms (EPS) at doses corresponding to low/moderate D2 occupancy. Such a decrease in the side effect incidence can be associated with its fast unbinding from D2 receptors in the nigrostriatal region allowing the recovery of dopamine signaling pathways. We performed docking essays using risperidone and the D3 receptor crystallographic data and results suggested two possible distinct orientations for risperidone at the binding pocket. Orientation 1 is more close to the opening of the binding site and has the 6-fluoro-1,2 benzoxazole fragment toward the bottom of the D3 receptor cleft, while orientation 2 is deeper inside the binding pocket with the same fragment toward to the receptor surface. In order to unveil the implications of these two binding orientations, classical molecular dynamics and quantum biochemistry computations within the density functional theory formalism and the molecular fractionation with conjugate caps framework were performed. Quantum mechanics/molecular mechanics suggests that orientation 2 (considering the contribution of Glu90) is slightly more energetically stable than orientation 1 with the main contribution coming from residue Asp110. The residue Glu90, positioned at the opening of the binding site, is closer to orientation 1 than 2, suggesting that it may have a key role in stability through attractive interaction with risperidone. Therefore, although orientations 1 and 2 are both likely to occur, we suggest that the occurrence of the first may contribute to the reduction of side effects in patients taking risperidone due to the reduction of dopamine receptor occupancy in the nigrostriatal region through a mechanism of fast dissociation. The atypical effect may be obtained simply by either delaying D3R full blockage by spatial hindrance of orientation 1 at the binding site or through an effective blockade followed by orientation 1 fast dissociation. While the molecular interpretation suggested in this work shed some light on the potential molecular mechanisms accounting for the reduced extrapyramidal symptoms observed during risperidone treatment, further studies are necessary in order to evaluate the implications of both orientations during the receptor activation/inhibition. Altogether these data highlight important hot spots in the dopamine receptor binding site bringing relevant information for the development of novel/derivative agents with atypical profile.

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.