Structural deformability induced in proteins of potential interest associated with COVID-19 by binding of homologues present in ivermectin: Comparative study based in elastic networks models.

The COVID-19 pandemic has accelerated the study of the potential of multi-target drugs (MTDs). The mixture of homologues called ivermectin (avermectin-B1a + avermectin-B1b) has been shown to be a MTD with potential antiviral activity against SARS-CoV-2 in vitro. However, there are few reports on the effect of each homologue on the flexibility and stiffness of proteins associated with COVID-19, described as ivermectin targets. We observed that each homologue was stably bound to the proteins studied and was able to induce detectable changes with Elastic Network Models (ENM). The perturbations induced by each homologue were characteristic of each compound and, in turn, were represented by a disruption of native intramolecular networks (interactions between residues). The homologues were able to slightly modify the conformation and stability of the connection points between the Cα atoms of the residues that make up the structural network of proteins (nodes), compared to free proteins. Each homologue was able to modified differently the distribution of quasi-rigid regions of the proteins, which could theoretically alter their biological activities. These results could provide a biophysical-computational view of the potential MTD mechanism that has been reported for ivermectin.

Stochastic Nature and Intramolecular Coupling in Optical Response Profiles: Critical Analysis through Semiclassical Models.

We have studied the nonlinear absorptive and dispersive responses considering a molecular system consisting of two-levels, where aspects of the vibrational internal structure and intramolecular coupling are inserted, in addition to the considerations of interaction with the thermal reservoir. The Born-Oppenheimer electronic energy curve for this molecular model consists of two-intercrossing harmonic oscillator potentials with minima displaced in energy and nuclear coordinate. The results obtained show how these optical responses are sensitive to explicit considerations of both intramolecular coupling and the presence of the solvent through their stochastic interaction. Our study shows that the permanent dipoles of the system and the transition dipoles induced by electromagnetic field effects represent critical quantities for the analysis. The solvent action in our model is treated through the natural Bohr frequency shift to a time-dependent function, with explicit manifestations in its comparison as if the upper state were broadened. Significant variations in the nonlinear optical properties for cases of perturbative and saturative treatments, relaxation times, and optical propagation, mainly due to changes in the probe and pump intensities, are studied. Our studies relating the intramolecular effects with those generated by the presence of the solvent and its stochastic interaction with the solute of study, have allowed not only to analyze the influence of these in the profile of the optical responses, but they could also provide some insights into the analysis and characterization of molecular systems through nonlinear optical properties.

Interaction of the new inhibitor paxlovid (PF-07321332) and ivermectin with the monomer of the main protease SARS-CoV-2: A volumetric study based on molecular dynamics, elastic networks, classical thermodynamics and SPT.

The COVID-19 pandemic has accelerated the study of drugs, most notably ivermectin and more recently Paxlovid (PF-07321332) which is in phase III clinical trials with experimental data showing covalent binding to the viral protease Mpro. Theoretical developments of catalytic site-directed docking support thermodynamically feasible non-covalent binding to Mpro. Here we show that Paxlovid binds non-covalently at regions other than the catalytic sites with energies stronger than reported and at the same binding site as the ivermectin B1a homologue, all through theoretical methodologies, including blind docking. We volumetrically characterize the non-covalent interaction of the ivermectin homologues (avermectins B1a and B1b) and Paxlovid with the mMpro monomer, through molecular dynamics and scaled particle theory (SPT). Using the fluctuation-dissipation theorem (FDT), we estimated the electric dipole moment fluctuations at the surface of each of complex involved in this study, with similar trends to that observed in the interaction volume. Using fluctuations of the intrinsic volume and the number of flexible fragments of proteins using anisotropic and Gaussian elastic networks (ANM+GNM) suggests the complexes with ivermectin are more dynamic and flexible than the unbound monomer. In contrast, the binding of Paxlovid to mMpro shows that the mMpro-PF complex is the least structurally dynamic of all the species measured in this investigation. The results support a differential molecular mechanism of the ivermectin and PF homologues in the mMpro monomer. Finally, the results showed that Paxlovid despite beingbound in different sites through covalent or non-covalent forms behaves similarly in terms of its structural flexibility and volumetric behaviour.

Comparative study of SARS-CoV-2 infection in different cell types: Biophysical-computational approach to the role of potential receptors.

Cellular susceptibility to SARS-CoV-2 infection in the respiratory tract has been associated with the ability of the virus to interact with potential receptors on the host membrane. We have modeled viral dynamics by simulating various cellular systems and artificial conditions, including macromolecular crowding, based on experimental and transcriptomic data to infer parameters associated with viral growth and predict cell susceptibility. We have accomplished this based on the type, number and level of expression of the angiotensin-converting enzyme 2 (ACE2), transmembrane serine 2 (TMPRSS2), basigin2 (CD147), FURIN protease, neuropilin 1 (NRP1) or other less studied candidate receptors such as heat shock protein A5 (HSPA5) and angiotensin II receptor type 2 (AGTR2). In parallel, we studied the effect of simulated artificial environments on the accessibility to said proposed receptors. In addition, viral kinetic behavior dependent on the degree of cellular susceptibility was predicted. The latter was observed to be more influenced by the type of proteins and expression level, than by the number of potential proteins associated with the SARS CoV-2 infection. We predict a greater theoretical propensity to susceptibility in cell lines such as NTERA-2, SCLC-21H, HepG2 and Vero6, and a lower theoretical propensity in lines such as CaLu3, RT4, HEK293, A549 and U-251MG. An important relationship was observed between expression levels, protein diffusivity, and thermodynamically favorable interactions between host proteins and the viral spike, suggesting potential sites of early infection other than the lungs. This research is expected to stimulate future quantitative experiments and promote systematic investigation of the effect of crowding presented here.

Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach.

The SARS-CoV-2 pandemic has accelerated the study of existing drugs. The mixture of homologs called ivermectin (avermectin-B1a [HB1a] + avermectin-B1b [HB1b]) has shown antiviral activity against SARS-CoV-2 in vitro. However, there are few reports on the behavior of each homolog. We investigated the interaction of each homolog with promising targets of interest associated with SARS-CoV-2 infection from a biophysical and computational-chemistry perspective using docking and molecular dynamics. We observed a differential behavior for each homolog, with an affinity of HB1b for viral structures, and of HB1a for host structures considered. The induced disturbances were differential and influenced by the hydrophobicity of each homolog and of the binding pockets. We present the first comparative analysis of the potential theoretical inhibitory effect of both avermectins on biomolecules associated with COVID-19, and suggest that ivermectin through its homologs, has a multiobjective behavior.

Tetradentate metal complexes derived from cephalexin and 2,6-diacetylpyridine bis(hydrazone): Synthesis, characterization and antibacterial activity.

Metal(II) coordination compounds of a hydrazone ligand (HL) derived from the condensation of cephalexin antibiotic with 2,6-diacetylpyridine bis(hydrazone) were synthesized. The hydrazone ligand and mononuclear [ML(H2O)2][PF6] (M(II)=Mn, Co, Ni, Zn) complexes were characterized by several techniques, including elemental and thermal analysis, molar conductance and magnetic susceptibility measurements, electronic, FT-IR, EPR and (1)H NMR spectral studies. The cephalexin 2,6-diacetylpyridine bis(hydrazone) ligand HL behaves as a monoanionic tetradentate NNNO chelating agent. The biological applications of complexes have been studied on two bacteria strains (Escherichia coli and Staphylococcus aureus) by agar diffusion disc method.