Computational development and validation of a representative MDI-BDO-based polyurethane hard segment model.

Segmented polyurethanes show extraordinary physicochemical properties, mainly owing to the nature and the chemistry of the hard segment domains. There are yet many inexplicable physiochemical properties of MDI-BDO-based hard polyurethane segments such as the geometry, cis-trans isomerism, electronic structure, chemical reactivity, the inter-hard-segment interactions, and the photo-response. In the present study, it was attempted to develop and validate a model system that would facilitate further research on the structural and chemical properties of the MDI-BDO hard segments. It was found that the trans isomer of urethane bond is more stable than the cis isomer, and it is argued here that thermal transformation from trans to cis not possible due to the high rotational energy barrier. The differences between the calculated IR spectra of the cis and trans isomers are proposed as a powerful differentiation tool. The calculated Fukui indices show that cis and trans isomers are different in their chemical reactivity. The findings of the present study suggest intermolecular and intramolecular pi-stacking and highly plausible two significant types of hydrogen bond types between hard segments. In the present study, a model system for MDI-BDO hard segment was developed and successfully validated via computational experiments. Further calculations done with the new model provided an indispensable understanding of the structure, cis-trans isomerism, reactivity, and intermolecular interactions of the MDI-BDO hard segments. The proposed model can be further improved in the future by incorporating suitable soft segments. In summary, the model system developed and validated in the present study has provided new opportunities to understand and further study the structural and chemical features of the hard segments of the MDI-BDO-based polyurethane.

Computational elucidation and validation of the three-dimensional structure of humanized aldolase catalytic antibody 38C2.

Catalytic antibodies are immunoglobulin proteins that are capable of catalyzing multiple reactions with diverse substrates. Aldolase catalytic antibody 38C2 catalyzes aldol and retro-aldol reactions via an enamine mechanism. Therefore, 38C2 has a high potential to be used in prodrug activation, and it is currently developed for selective chemotherapy. For medical applications, its humanization is essential, and therefore, the understanding of the three-dimensional (3D) spatial atomistic structure of 38C2 is mandatory. In this study, it was attempted to construct the 3D atomic structure of humanized abzyme 38C2 using computational methods. A homology modeled structure was simulated for 100 ns with classical molecular dynamics simulations for its dynamics stability. The accuracy of the constructed model was further evaluated with various theoretical methods. The binding of four selected natural substrates to the constructed structure was studied in detail to further validate the model. Finally, to evaluate the reaction readiness of the constructed protein, the first step of the catalytic reaction has been successfully carried out with QST3/IRC calculations using the DFT/B3LYP-6-31G level of theory in the presence of extracted catalytic residues with the preserved coordinates in implicit water. Hence, the reaction readiness of the proposed protein structure, along with all the other validation tests, strongly proves that the modeled structure has high accuracy. This study, therefore, sheds new light on the structure, mechanism of action and applications of the 38C2 abzyme by constructing and validating its full 3D atomistic model. Further, this highly reliable modeled structure will expedite and facilitate future 38C2-based drug discovery.Communicated by Ramaswamy H. Sarma.

Bergenin: a computationally proven promising scaffold for novel galectin-3 inhibitors.

Bergenin is a C-glycoside of 4-O-methylgallic acid that is isolated from medicinal plants such as Flueggea leucopyrus, Bergenia crassifolia, Mallotus philippensis, Corylopsis spicata, Caesalpinia digyna, Mallotus japonicus, and Sacoglottis gabonensis. Even though there appears to be ample evidence from South Asian traditional medicine that bergenin possesses strong anticancer activity, no comprehensive scientific study has been carried out to test its anticancer potency. Therefore, in this study, the potential mechanisms of action for bergenin's postulated anticancer activity were examined using computational techniques. Firstly, bergenin was tested for its toxicity as a drug candidate using in silico toxicity analysis. It was found that bergenin is nontoxic according to modern toxicity measures. The optimized structure of bergenin was obtained at the DFT-B3LYP/6-31G(d) level of theory. Potential biological targets of bergenin were identified using reverse docking calculations. Reverse docking results suggested that galectin-3 is a potential target of bergenin. Gelectin-3 is an enzyme that plays a major role in cell-cell adhesion, cell-matrix interactions, macrophage activation, angiogenesis, metastasis, and apoptosis in cancer, making it a popular target in anticancer drug design. Among the many potential biological targets predicted by reverse docking calculations, galectin-3 was selected as it complies with the primary objective of this study. The binding of bergenin to galectin-3 was studied by conventional forward docking calculations. Classical molecular dynamics (MD) simulations were used to study the stability of the galectin-3:bergenin complex. Docking calculations indicated that bergenin has the potential to effectively bind to the carbohydrate recognition domain (CRD) of galectin-3. As well as electrostatic and van der Waals interactions, a few strong hydrogen bonds were found to be involved in the binding of bergenin to galectin-3. There is also a plausible π-stacking interaction between the aromatic moiety of bergenin and the His158 residue at the binding site. A 50-ns MD simulation was carried out for the bergenin:galectin-3 complex in a cubic water box with periodic boundary conditions. The MD results showed that the bergenin:galectin-3 complex is highly stable and confirmed the veracity of the docking results, which suggested that bergenin potentially exerts an inhibitory effect on galectin-3. This study therefore sheds new light on the anticancer activity of bergenin and demonstrates that bergenin could potentially be used to develop more potent galectin-3 inhibitors. The study also provides scientific evidence supporting the use of bergenin-containing plants in cancer treatments in Eastern traditional medicine. Graphical abstract Bergenin in the galectin-3 binding site.