Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach.

The rapid emergence and spread of new variants of coronavirus type 2, as well as the emergence of zoonotic viruses, highlights the need for methodologies that contribute to the search for new pharmacological treatments. In the present work, we searched for new SARS-CoV-2 papain-like protease inhibitors in the PubChem database, which has more than 100 million compounds. Based on the ligand efficacy index obtained by molecular docking, 500 compounds with higher affinity than another experimentally tested inhibitor were selected. Finally, the seven compounds with ADME parameters within the acceptable range for such a drug were selected. Next, molecular dynamics simulation studies at 200 ns, ΔG calculations using molecular mechanics with generalized Born and surface solvation, and quantum mechanical calculations were performed with the selected compounds. Using this in silico protocol, seven papain-like protease inhibitors are proposed: three compounds with similar free energy (D28, D04, and D59) and three compounds with higher binding free energy (D60, D99, and D06) than the experimentally tested inhibitor, plus one compound (D24) that could bind to the ubiquitin-binding region and reduce the effect on the host immune system. The proposed compounds could be used in in vitro assays, and the described protocol could be used for smart drug design.

Mesoscopic Modeling of the Encapsulation of Capsaicin by Lecithin/Chitosan Liposomal Nanoparticles.

The transport of hydrophobic drugs in the human body exhibits complications due to the low solubility of these compounds. With the purpose of enhancing the bioavailability and biodistribution of such drugs, recent studies have reported the use of amphiphilic molecules, such as phospholipids, for the synthesis of nanoparticles or nanocapsules. Given that phospholipids can self-assemble in liposomes or micellar structures, they are ideal candidates to function as vehicles of hydrophobic molecules. In this work, we report mesoscopic simulations of nanoliposomes, constituted by lecithin and coated with a shell of chitosan. The stability of such structures and the efficiency of the encapsulation of capsaicin, as well as the internal and superficial distribution of capsaicin and chitosan inside the nanoliposome, were analyzed. The characterization of the system was carried out through density maps and the potentials of mean force for the lecithin-capsaicin, lecithin-chitosan, and capsaicin-chitosan interactions. The results of these simulations show that chitosan is deposited on the surface of the nanoliposome, as has been reported in some experimental works. It was also observed that a nanoliposome of approximately 18 nm in diameter is stable during the simulation. The deposition behavior was found to be influenced by a pattern of N-acetylation of chitosan.

1H NMR studies of molecular interaction of D-glucosamine and N-acetyl-D-glucosamine with capsaicin in aqueous and non-aqueous media.

Complex formation of D-glucosamine (Gl) and N-acetyl-D-glucosamine (AGl) with capsaicin (Cp) were studied by 1H NMR titrations in H2O-d2 and DMSO-d6; capsaicin is the major bioactive component of chili peppers. Every titration curve has been interpreted by formulating a suitable model for the reaction equilibrium, to elucidate intermolecular interactions. In DMSO, glucosamine cations associate with each other to yield linear aggregates, and undergo pseudo-1:1-complexation with capsaicin, the formation constant being ca. 30 M-1. N-Acetylglucosamine, without self-association, forms a 2:1-complex AGl2Cp with the stability of ca. 70 M-2. These complexations are achieved by intermolecular hydrogen bonds. In D2O, glucosamine undergoes reversible protonation equilibrium between Gl0 and GlH+ with the logarithmic protonation constants log KD = 8.63 for α-glucosamine and 8.20 for ß-isomer. Both anomeric isomers of deprotonated glucosamine form Gl0Cp-type complexes of capsaicin, in a competitive manner, with a formation constant of 1040 M-1 for the α-glucosamine complex and 830 M-1 for the ß-complex; the anomeric carbons result in the difference in thermodynamic stability. The reactant molecules are closed up by the solvent-exclusion effect and/or the van der Waals interaction; the resulting pair is stabilized by intermolecular hydrogen bonding within a local water-free space between the component molecules. By contrast, neither protonated glucosamine (GlH+) nor N-acetylglucosamine yields a capsaicin complex with the definite stoichiometry. The monosaccharides recognize capsaicin under only a controlled condition; the same phenomena are predicted for biological systems and nanocarriers based on polysaccharides such as chitosan.

Desorption of hydrocarbon chains by association with ionic and nonionic surfactants under flow as a mechanism for enhanced oil recovery.

The need to extract oil from wells where it is embedded on the surfaces of rocks has led to the development of new and improved enhanced oil recovery techniques. One of those is the injection of surfactants with water vapor, which promotes desorption of oil that can then be extracted using pumps, as the surfactants encapsulate the oil in foams. However, the mechanisms that lead to the optimal desorption of oil and the best type of surfactants to carry out desorption are not well known yet, which warrants the need to carry out basic research on this topic. In this work, we report non equilibrium dissipative particle dynamics simulations of model surfactants and oil molecules adsorbed on surfaces, with the purpose of studying the efficiency of the surfactants to desorb hydrocarbon chains, that are found adsorbed over flat surfaces. The model surfactants studied correspond to nonionic and cationic surfactants, and the hydrocarbon desorption is studied as a function of surfactant concentration under increasing Poiseuille flow. We obtain various hydrocarbon desorption isotherms for every model of surfactant proposed, under flow. Nonionic surfactants are found to be the most effective to desorb oil and the mechanisms that lead to this phenomenon are presented and discussed.

Electrostatics in dissipative particle dynamics using Ewald sums with point charges.

A proper treatment of electrostatic interactions is crucial for the accurate calculation of forces in computer simulations. Electrostatic interactions are typically modeled using Ewald-based methods, which have become some of the cornerstones upon which many other methods for the numerical computation of electrostatic interactions are based. However, their use with charge distributions rather than point charges requires the inclusion of ansatz for the solutions of the Poisson equation, since there is no exact solution known for smeared out charges. The interest in incorporating electrostatic interactions at the scales of length and time that are relevant for the study the physics of soft condensed matter has increased considerably. Using mesoscale simulation techniques, such as dissipative particle dynamics (DPD), allows us to reach longer time scales in numerical simulations, without abandoning the particulate description of the problem. The main problem with incorporating electrostatics into DPD simulations is that DPD particles are soft and those particles with opposite charge can form artificial clusters of ions. Here we show that one can incorporate the electrostatic interactions through Ewald sums with point charges in DPD if larger values of coarse-graining degree are used, where DPD is truly mesoscopic. Using point charges with larger excluded volume interactions, the artificial formation of ionic pairs with point charges can be avoided and one obtains correct predictions. We establish ranges of parameters useful for detecting boundaries where artificial formation of ionic pairs occurs. Lastly, using point charges we predict the scaling properties of polyelectrolytes in solvents of varying quality, and obtain predictions that are in agreement with calculations that use other methods and with recent experimental results.

Mesoscopic modeling of structural and thermodynamic properties of fluids confined by rough surfaces.

The interfacial and structural properties of fluids confined by surfaces of different geometries are studied at the mesoscopic scale using dissipative particle dynamics simulations in the grand canonical ensemble. The structure of the surfaces is modeled by a simple function, which allows us to simulate readily different types of surfaces through the choice of three parameters only. The fluids we have modeled are confined either by two smooth surfaces or by symmetrically and asymmetrically structured walls. We calculate structural and thermodynamic properties such as the density, temperature and pressure profiles, as well as the interfacial tension profiles for each case and find that a structural order-disorder phase transition occurs as the degree of surface roughness increases. However, the magnitude of the interfacial tension is insensitive to the structuring of the surfaces and depends solely on the magnitude of the solid-fluid interaction. These results are important for modern nanotechnology applications, such as in the enhanced recovery of oil, and in the design of porous materials with specifically tailored properties.

Molecular dynamics simulations of 2-(dimethylamino)ethanol (DMEA).

We develop a multipurpose force field to investigate the properties of the condensed phases of 2-(dimethylamino)ethanol (DMEA). We use ab initio computations at the HF/6-311++G(2d,2p) level to derive partial charges, obtain force constants, and compute the electrostatic potential of the DMEA. We find that the HF predictions for the dipole moment are in excellent agreement with the experimental result (2.6 D). The computations also show the strong preference of DMEA to form intramolecular hydrogen bonds between the hydrogen in the alcohol group and nitrogen. We have tested the accuracy of our force field by computing coexistence and interfacial properties as well as thermal conductivities in wide range of thermodynamic states. In all these instances we find excellent agreement with the available experimental data. We have further investigated the structure of the liquid by computing pair correlations. Our results indicate a clear preference for DMEA to form low-dimensional structures, such as linear and bifurcated chains, which are driven by the association of the DMEA molecules via the alcohol group. Overall, our force field provides a good basis to compute the bulk and interfacial properties of DMEA.

Modeling conformational ensembles of slow functional motions in Pin1-WW.

Protein-protein interactions are often mediated by flexible loops that experience conformational dynamics on the microsecond to millisecond time scales. NMR relaxation studies can map these dynamics. However, defining the network of inter-converting conformers that underlie the relaxation data remains generally challenging. Here, we combine NMR relaxation experiments with simulation to visualize networks of inter-converting conformers. We demonstrate our approach with the apo Pin1-WW domain, for which NMR has revealed conformational dynamics of a flexible loop in the millisecond range. We sample and cluster the free energy landscape using Markov State Models (MSM) with major and minor exchange states with high correlation with the NMR relaxation data and low NOE violations. These MSM are hierarchical ensembles of slowly interconverting, metastable macrostates and rapidly interconverting microstates. We found a low population state that consists primarily of holo-like conformations and is a "hub" visited by most pathways between macrostates. These results suggest that conformational equilibria between holo-like and alternative conformers pre-exist in the intrinsic dynamics of apo Pin1-WW. Analysis using MutInf, a mutual information method for quantifying correlated motions, reveals that WW dynamics not only play a role in substrate recognition, but also may help couple the substrate binding site on the WW domain to the one on the catalytic domain. Our work represents an important step towards building networks of inter-converting conformational states and is generally applicable.

Molecular dynamics simulations of aqueous solutions of ethanolamines.

We report on molecular dynamics simulations performed at constant temperature and pressure to study ethanolamines as pure components and in aqueous solutions. A new geometric integration algorithm that preserves the correct phase space volume is employed to study molecules having up to three ethanol chains. The most stable geometry, rotational barriers, and atomic charges were obtained by ab initio calculations in the gas phase. The calculated dipole moments agree well with available experimental data. The most stable conformation, due to intramolecular hydrogen bonding interactions, has a ringlike structure in one of the ethanol chains, leading to high molecular stability. All molecular dynamics simulations were performed in the liquid phase. The interaction parameters are the same for the atoms in the ethanol chains, reducing the number of variables in the potential model. Intermolecular hydrogen bonding is also analyzed, and it is shown that water associates at low water mole fractions. The force field reproduced (within 1%) the experimental liquid densities at different temperatures of pure components and aqueous solutions at 313 K. The excess and partial molar volumes are analyzed as a function of ethanolamine concentration.