Computational Insights into Bio-relevant Sulfur Chemistry

Sulfur-containing molecules are chemically and functionally versatile compounds, exemplified by their diverse roles from enzymatic processes to organic synthesis and drug design. With the goal of gaining detailed and deeper insights into the chemistry of such species, multi-scale computational modeling techniques we have applied in this work. Chapter 1 provides a brief summary of the importance of sulfur, its functionality, and reactivity in biological systems including catalytic environments such as enzymes. In Chapter 2, an overview of the key features of the common and contemporary computational approaches is explained briefly. In Chapter 3, systematic benchmark studies are performed to determine reliable and accurate structures as well as thermochemical data for a series of bio-relevant polysulfur/ selenium-containing compounds. Of the variety of DFT functionals and Pople basis sets examined, the ωB97XD/6-311G(2d,p) level of theory is found to generally give the most accurate and reliable results. Furthermore, S—S bond lengths are more sensitive to the choice of basis set than those containing Se. Comparison of the proton affinities and gas-phase basicities of thiols and their corresponding persulfide derivatives indicates that extending the sulfur chain decreases their values, suggesting that polysulfur species exist as deprotonated species in biological systems. In Chapter 4, the roles of solvent choice on the possible mechanisms of formation of sulfonamides via the reaction of SO2 and N-tosyl hydrazone using DFT-based methods in combination with implicit and hybrid implicit/explicit solvation models is examined. The results indicate that solvent-solute interactions can play critical roles in such reactions. Of the solvents considered, DMSO and piperidine are found to be the most effective (i.e., actively involved) facilitating sulfonamide bond formation. Applying DFT and conventional ab initio methods, Chapter 5 examines the formation of SO2-containing molecules including sulfones, sulfonamides, and sulfamides via the radical-based reaction of SO2 with a systematic series of xiamycin-inspired aromatic C- and N-centered radicals. A preference for C–S(O2) vs. N–S(O2) bond formation is observed with formation of sulfones being thermodynamically preferred to sulfamides. Also, of the DFT functionals used, the M06-2X functional was shown to be most reliable for providing optimized geometries and relative energies of the SO2-containing species examined. In Chapter 6, the formation of a range of possible HNO-derived post-translational modifications of cysteinyl and cysteinyl persulfide was examined using DFT-based methods. It is shown that the formation of the initial -X-NHOH (X=S, S-S) containing intermediate is independent of the residues position in the peptide while their subsequent reaction and final PTM formed is dependent on the residues position. More specifically, reaction of HNO with N-terminus or internal residues leads to formation of disulfide or sulfonamide (e.g., Cys-SS-Cys or Cys-S(O)-NH2) via rearrangement and nucleophilic substitutions, respectively. Meanwhile, Cys-X-NH2 derived from C-terminus peptide leads to Cys-X-OH formation through the intermediacy of a 5- or 6-membered cyclic intermediates in cystenyl and cystenyl persulfide, respectively. In Chapter 7 we examine the active site, substrate binding, and catalytic mechanism of the bacterial Ni(II)-dimethylsulfoniopropionate (DMSP) lyase (DddK) enzyme. The findings show that two active site tyrosyls (Tyr64 and 122) play significant roles in substrate binding, with Tyr64 also acting as a Lewis base to initiate the β-concerted elimination reaction to form the dimethyl sulfide product. In Chapter 8 we examine, using a multi-scale computational approach, a possible disulfidesulfenylamide shuttling mechanism in the active site of DAH7PS enzyme. The results imply the key role of the metal ion (Mn(II)) and acidic environment in the potential interconversion between these conformations. Our findings infer that the preference of the cyclic sulfenylamide conformation to disulfide in the enzyme active site switches to the preference of disulfide to cyclic sulfenylamide conformation in the absence of metal ions and/or providing an acidic environment

An Assessment of Computational Methods for Calculating Accurate Structures and Energies of Bio-Relevant Polysulfur/Selenium-Containing Compounds

The heavier chalcogens sulfur and selenium are important in organic and inorganic chemistry, and the role of such chalcogens in biological systems has recently gained more attention. Sulfur and, to a lesser extent selenium, are involved in diverse reactions from redox signaling to antioxidant activity and are considered essential nutrients. We investigated the ability of the DFT functionals (B3LYP, B3PW91, ωB97XD, M06-2X, and M08-HX) relative to electron correlation methods MP2 and QCISD to produce reliable and accurate structures as well as thermochemical data for sulfur/selenium-containing systems. Bond lengths, proton affinities (PA), gas phase basicities (GPB), chalcogen–chalcogen bond dissociation enthalpies (BDE), and the hydrogen affinities (HA) of thiyl/selenyl radicals were evaluated for a range of small polysulfur/selenium compounds and cysteine per/polysulfide. The S–S bond length was found to be the most sensitive to basis set choice, while the geometry of selenium-containing compounds was less sensitive to basis set. In mixed chalcogens species of sulfur and selenium, the location of the sulfur atom affects the S–Se bond length as it can hold more negative charge. PA, GPB, BDE, and HA of selenium systems were all lower, indicating more acidity and more stability of radicals. Extending the sulfur chain in cysteine results in a decrease of BDE and HA, but these plateau at a certain point (199 kJ mol−1 and 295 kJ mol−1), and PA and GPB are also decreased relative to the thiol, indicating that the polysulfur species exist as thiolates in a biological system. In general, it was found that ωB97XD/6-311G(2d,p) gave the most reasonable structures and thermochemistry relative to benchmark calculations. However, nuances in performance are observed and discussed

Generation and Reactions of a Benzodehydrotropylium Ion-Co2(CO)6 Complex

A series of 7-methylenedehydrobenzo[7]annulen-5-ol hexacarbonyldicobalt complexes were generated by Hosomi-Sakurai reactions of allylsilanes containing o-alkynylarylaldehyde-Co2(CO)6 complexes. One of cyclization products was converted into its corresponding dihydrobenzo[7]annulen-7-ol hexacarbonyldicobalt complex, an immediate precursor to a benzodehydrotropylium-Co2(CO)6. The cation was generated in situ and reacted with four nucleophiles, and its aromatic stabilization determined by computational methods

Elevated Serum Levels of Interleukin-15 in Pemphigus Vulgaris Patients: a Potential Therapeutic Target

Introduction: Pemphigus vulgaris (PV) is a rare autoimmune disease that causes painful blistering. Interleukin-15 (IL-15) as a member of the immunoregulatory cytokines family is associated with the development of the chronic inflammatory or autoimmune disease. There is not much information available in the literature on the exact role IL-15 plays in PV. Objectives: The goal of this study was to evaluate the serum levels of IL-15 in patients with PV and assess the association of IL-15 with anti-desmoglein antibodies and the severity of the disease. Methods: Fifty-three individuals affected with active PV and 38 age- and gender-matched healthy controls were participated in this study. Disease severity was assessed using Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). Serum levels of IL-15 (pg/mL) and anti-desmoglein antibodies (Dsg1, 3) were determined. Results: In the patient group, IL-15 serum levels were statistically higher than those in the control group (3.71 } 1.5 vs. 0.79 } 1.03, P \u3c 0.001). A positive correlation was found between serum levels of IL-15 and ABSIS (r = 0.5, P = 0.04). We found no significant correlation between serum concentrations of IL-15 and antidesmoglein antibodies (Dsg1 or Dsg3). Conclusions: An increase in serum level of IL-15 in patients with PV and its relationship with disease severity suggest that this cytokine possibly contributes to the pathogenesis of the disease and targeting IL-15 will likely provide a new insight into the treatment of this disease

Evidence for an Allosteric S-Nitrosoglutathione Binding Site in S-Nitrosoglutathione Reductase (GSNOR)

Current research has identified S-nitrosoglutathione reductase (GSNOR) as the central enzyme for regulating protein S-nitrosylation. In addition, the dysregulation of GSNOR expression is implicated in several organ system pathologies including respiratory, cardiovascular, hematologic, and neurologic, making GSNOR a primary target for pharmacological intervention. This study demonstrates the kinetic activation of GSNOR by its substrate S-nitrosoglutathione (GSNO). GSNOR kinetic analysis data resulted in nonhyperbolic behavior that was successfully accommodated by the Hill–Langmuir equation with a Hill coefficient of +1.75, indicating that the substrate, GSNO, was acting as a positive allosteric affector. Docking and molecular dynamics simulations were used to predict the location of the GSNO allosteric domain comprising the residues Asn185, Lys188, Gly321, and Lys323 in the vicinity of the structural Zn2+-binding site. GSNO binding to Lys188, Gly321, and Lys323 was further supported by hydrogen–deuterium exchange mass spectroscopy (HDXMS), as deuterium exchange significantly decreased at these residues in the presence of GSNO. The site-directed mutagenesis of Lys188Ala and Lys323Ala resulted in the loss of allosteric behavior. Ultimately, this work unambiguously demonstrates that GSNO at large concentrations activates GSNOR by binding to an allosteric site comprised of the residues Asn185, Lys188, Gly321, and Lys323. The identification of an allosteric GSNO-binding domain on GSNOR is significant, as it provides a platform for pharmacological intervention to modulate the activity of this essential enzyme

Antiviral Therapeutic Potential of Curcumin: An Update

The treatment of viral disease has become a medical challenge because of the increasing incidence and prevalence of human viral pathogens, as well as the lack of viable treatment alternatives, including plant-derived strategies. This review attempts to investigate the trends of research on in vitro antiviral effects of curcumin against different classes of human viral pathogens worldwide. Various electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar were searched for published English articles evaluating the anti-viral activity of curcumin. Data were then extracted and analyzed. The forty-three studies (published from 1993 to 2020) that were identified contain data for 24 different viruses. The 50% cytotoxic concentration (CC50), 50% effective/inhibitory concentration (EC50/IC50), and stimulation index (SI) parameters showed that curcumin had antiviral activity against viruses causing diseases in humans. Data presented in this review highlight the potential antiviral applications of curcumin and open new avenues for further experiments on the clinical applications of curcumin and its derivatives

Antiviral Therapeutic Potential of Curcumin: An Update

The treatment of viral disease has become a medical challenge because of the increasing incidence and prevalence of human viral pathogens, as well as the lack of viable treatment alternatives, including plant-derived strategies. This review attempts to investigate the trends of research on in vitro antiviral effects of curcumin against different classes of human viral pathogens worldwide. Various electronic databases, including PubMed, Scopus, Web of Science, and Google Scholar were searched for published English articles evaluating the anti-viral activity of curcumin. Data were then extracted and analyzed. The forty-three studies (published from 1993 to 2020) that were identified contain data for 24 different viruses. The 50% cytotoxic concentration (CC50), 50% effective/inhibitory concentration (EC50/IC50), and stimulation index (SI) parameters showed that curcumin had antiviral activity against viruses causing diseases in humans. Data presented in this review highlight the potential antiviral applications of curcumin and open new avenues for further experiments on the clinical applications of curcumin and its derivatives