Redox processes are important in chemistry, with applications in biomedicine, chemical analysis, among others. As many redox experiments are also performed at a fixed value of pH, having an efficient computational method to support experimental measures at both constant redox potential and pH is very important. Such computational techniques have the potential to validate experimental observations performed under these conditions and to provide additional information unachievable experimentally such as an atomic level description of macroscopic measures. We present the implementation of discrete redox and protonation states methods for constant redox potential Molecular Dynamics (CEMD), for coupled constant pH and constant redox potential MD (C(pH,E)MD), and for Replica Exchange MD along the redox potential dimension (E-REMD) on the AMBER software package. Validation results are presented for a small system that contains a single heme group: -acetylmicroperoxidase-8 (NAcMP8) axially connected to a histidine peptide. The methods implemented allow one to make standard redox potential (E) predictions with the same easiness and accuracy as p predictions using the constant pH molecular dynamics and pH-REMD methods currently available on AMBER. In our simulations, we can correctly describe, in agreement also with theoretical predictions, the following behaviors: when a redox-active group is reduced, the p of a near pH-active group increases because it becomes easier for a proton to be attached; equivalently, when a pH-active group is protonated, the standard redox potential (E) of an adjacent redox-active group rises. Furthermore, our results also show that E-REMD is able to achieve faster statistical convergence than CEMD or C(pH,E)MD. Moreover, computational benchmarks using our methodologies show high-performance of GPU (Graphics Processing Unit) accelerated calculations in comparison to conventional CPU (Central Processing Unit) calculations.

a b s t r a c tThe sequential Monte Carlo/CASPT2 approach was employed to investigate deactivation and emission processes from the lowest-lying pp * and np * excited states of 9H-adenine in aqueous solution. It is found that conical intersections connecting the pp* and np* states with the ground state are also present in solution, whereas the barriers for the deactivation paths are significantly smaller on solvated conditions. The large destabilization of the np* state found in solution possibly prevents its involvement in the deactivation photophysics and explains the change from a bi-to a mono-exponential decay for the molecule in the gas phase and solution, respectively.

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

Studies examining various spacer groups that link the two aromatic rings of combretastatin A-4 (CA4) have shown that the biological activity of analogs does not require the cis-stilbene configuration of CA4. Oxygen or nitrogen, carbonyl, methylene and ethylene spacers, for example, are present in CA4 analogs that show good activity. Up to now sulfur was not tested for this purpose. In this article we describe the synthesis of sulfide, sulfoxide and sulfone spacers between two aromatic rings comparable to those of CA4. We also compared them with CA4 for inhibitory effects on cell growth, tubulin polymerization, and the binding of [ 3 H]colchicine to tubulin. We found that the sulfide is highly active and may be a lead compound for the preparation of antitumor compounds.

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The potential outcome of flavivirus and alphavirus co-infections is worrisome due to the development of severe diseases. Hundreds of millions of people worldwide live under the risk of infections caused by viruses like chikungunya virus (CHIKV, genus Alphavirus), dengue virus (DENV, genus Flavivirus), and zika virus (ZIKV, genus Flavivirus). So far, neither any drug exists against the infection by a single virus, nor against co-infection. The results described in our study demonstrate the inhibitory potential of two flavonoids derived from citrus plants: Hesperetin (HST) against NS2B/NS3pro of ZIKV and nsP2pro of CHIKV and, Hesperidin (HSD) against nsP2pro of CHIKV. The flavonoids are noncompetitive inhibitors and the determined IC50 values are in low µM range for HST against ZIKV NS2B/NS3pro (12.6 ± 1.3 µM) and against CHIKV nsP2pro (2.5 ± 0.4 µM). The IC50 for HSD against CHIKV nsP2pro was 7.1 ± 1.1 µM. The calculated ligand efficiencies for HST were > 0.3, which reflect its potential to be used as a lead compound. Docking and molecular dynamics simulations display the effect of HST and HSD on the protease 3D models of CHIKV and ZIKV. Conformational changes after ligand binding and their effect on the substrate-binding pocket of the proteases were investigated. Additionally, MTT assays demonstrated a very low cytotoxicity of both the molecules. Based on our results, we assume that HST comprise a chemical structure that serves as a starting point molecule to develop a potent inhibitor to combat CHIKV and ZIKV co-infections by inhibiting the virus proteases.