Santalol Isomers Inhibit Transthyretin Amyloidogenesis and Associated Pathologies in Caenorhabditis elegans.

Transthyretin (TTR) is a homotetrameric protein found in human serum and is implicated in fatal inherited amyloidoses. Destabilization of native TTR confirmation resulting from mutation, environmental changes, and aging causes polymerization and amyloid fibril formation. Although several small molecules have been reported to stabilize the native state and inhibit TTR aggregation, prolonged use can cause serious side effects. Therefore, pharmacologically enhancing the degradation of TTR aggregates and kinetically stabilizing the native tetrameric structure with bioactive molecule(s) could be a viable therapeutic strategy to hinder the advancement of TTR amyloidoses. In this context, here we demonstrated α- and ß-santalol, natural sesquiterpenes from sandalwood, as a potent TTR aggregation inhibitor and native state stabilizer using combined in vitro, in silico, and in vivo experiments. We found that α- and ß-santalol synergize to reduce wild-type (WT) and Val30Met (V30M) mutant TTR aggregates in novel C. elegans strains expressing TTR fragments fused with a green fluorescent protein in body wall muscle cells. α- and ß-Santalol extend the lifespan and healthspan of C. elegans strains carrying TTRWT::EGFP and TTRV30M::EGFP transgene by activating the SKN-1/Nrf2, autophagy, and proteasome. Moreover, α- and ß-santalol directly interacted with TTR and reduced the flexibility of the thyroxine-binding cavity and homotetramer interface, which in turn increases stability and prevents the dissociation of the TTR tetramer. These data indicate that α- and ß-santalol are the strong natural therapeutic intervention against TTR-associated amyloid diseases.

In silico studies of the inhibition mechanism of dengue with papain.

Dengue virus is becoming a major global disease; the envelope protein is the major target for vaccine development against Dengue. Nowadays, the attention has focused on developing inhibitors based on Papain is a promising target for treating Dengue. In the present work, the theoretical studies of E-protein(Cys74-Glu79;Lys110)…Papain(Cys25, Asn175 and His159) complexes are analysed by Density Functional Theory (M06-2X/cc-pVDZ) method. Among the E-protein(Cys74-Glu79;Lys110)…Papain(Cys25, Asn175 and Hys159) complexes, E-protein(Glu76)…Papain(Cys25) complex has the highest interaction value of -352.22 kcal/mol. Moreover, the natural bond orbital analysis also supports the above results. The 100 ns Molecular Dynamics simulation reveals that, E-protein(Ala54-Ile129)…Papain(Cys25) complex had the lowest root mean square deviation value of 1 Å compared to the E-protein(Ala54-Ile129)… Papain(Asn175 & His159) complexes. The salt bridge formation between the Asp103 and Lys110 residues are the important stabilizing factor in E-protein(Ala54-Ile129)…Papain(Cys25) complex. This result can extend our knowledge of the functional behaviour of Papain and provides structural insight to target Envelope protein as forthcoming drug targets in Dengue.

The hazardous effects of the environmental toxic gases on amyloid beta-peptide aggregation: A theoretical perspective.

Alzheimer's disease (AD) is one of the leading causes of dementia in elderly people. It has been well documented that the exposure to environmental toxins such as CO, CO2, SO2 and NO2 that are present in the air is considered as a hallmark for the progression of Alzheimer's disease. However, their actual mechanism by which environmental toxin triggers the aggregation of Aß42 peptide at the molecular and atomic levels remain unknown. In this study, molecular dynamics simulation was carried out to study the aggregation mechanism of the Aß42 peptide due to its interaction of toxic gas (CO, CO2, SO2 and NO2). During the 400 ns simulation, all the Aß42 interacted toxic gas (CO, CO2, SO2, and NO2) complexes have smaller Root Mean Square Deviation values when compared to the Aß42 peptide, which shows that the interaction of toxic gases (CO, CO2, SO2, and NO2) would increase the Aß42 peptide structural stability. The radius of gyration analysis also supports that Aß42 interacted CO2 and SO2 complexes have the minimum value in the range of 0.95 nm and 1.5 nm. It is accounted that the Aß42 interacted CO2 and SO2 complexes have a greater compact structure in comparison to Aß42 interacted CO and NO2 complexes. Furthermore, all the Aß42 interacted toxic gas (CO, CO2, SO2, and NO2) complexes exhibited an enhanced secondary structural probability for coil and turn regions with a reduced α-helix probability, which indicates that the interaction of toxic gases may enhance the toxicity and aggregation of Aß42.

Modeling of Si-B-N Sheets and Derivatives as a Potential Sorbent Material for the Adsorption of Li+ Ion and CO2 Gas Molecule.

In the present exploration, a few Si-B-N derivatives are derived to adsorb Li ions and CO2 gas molecules for the potential application of metal-air batteries. The newly derived structure's bond lengths are as follows: Si=Si, 2.2 Å; Si-B, 1.9 Å; Si-N, 1.7 Å; and B-N, 1.4 Å, consistent with the experimental results of relevant structures. The stability of the newly derived structures is examined by the atom-centered density propagation study by varying the temperature from 270 to 400 K, and no structural variations are observed throughout the dynamics. Li adsorption on the Si4B2 ring has the maximum binding energy of -3.9 eV, and the result is consistent with the previous results. The rings with the 2:1 silicon-boron ratio provide strong adsorption for Li atoms. The calculated maximum electromotive force of the newly derived sheets is 0.56 V with the maximum theoretical density of 783 Wh/kg. Similarly, the maximum adsorption of CO2 on the sheet is -0.106 eV, which is considerably higher than that on graphene and its derivatives. CO2 adsorption has been carried out in the presence of water molecules to investigate the change in CO2 adsorption with the moisture (water) content, and the results show no significant change in the adsorption of CO2 with moisture. However, water has a strong interaction with the maximum interaction energy of -0.72 eV. Further, to explore the potential ability of the sheets, each sheet's edges are examined as hydrogen storage expedient and the surface as an artificial photosynthesis platform. The Si4B2 ring is more favorable for the adsorption of H atom with the chemisorption of -7.138 eV. Similarly, all of the major UV-absorption spectral peaks fall between 450 and 800 nm, which shows that the sheet can be used as an artificial photosynthesis platform.

EMBM - a new enzyme mechanism-based method for rational design of chemical sites of covalent inhibitors.

We introduce an enzyme mechanism-based method (EMBM) aimed at rational design of chemical sites (CS) of reaction coordinate analog inhibitors. The energy of valence reorganization of CS, caused by the formation of the enzyme-inhibitor covalent complex, is accounted for by new covalent descriptors W1 and W2. We considered CS fragments with a carbonyl reactivity center, like in native protease substrates. The W1 and W2 descriptors are calculated quantum mechanically on small molecular clusters simulating the reaction core of the formed covalent tetrahedral complex, anionic TC(O-) or neutral TC(OH). The modeling on a reaction core allows generation of various CS and corresponding TC(O-) and TC(OH) as universal building blocks of real inhibitors and their covalent complexes with serine or cysteine hydrolases. Moreover, the approach avoids the need for 3D structure of the target enzyme, so EMBM may be used for ligand-based design. We have built a chemical site of inhibitors (CSI) databank with pairs of W1 and W2 descriptors precalculated for both CH3O(-) and CH3S(-) nucleophiles for every collected CS fragment. We demonstrated that contribution of a CS fragment to the binding affinity of an inhibitor depends on both its covalent reorganization during the chemical transformation and its noncovalent interactions in the enzyme active site. Consequently, prediction of inhibitors binding trend can be done only by accounting for all of these factors, using W1 and W2 in combination with noncovalent QSAR descriptors.