Chemical Informatics

Description

It has been demonstrated that interpreting genomic variants for disease risk and predicting the effects of single amino acid substitutions in protein engineering depend heavily on calculating changes in protein stability. Although the tools used to calculate Gs were developed on experimentally resolved structures, structure-based calculations are considered to be the most accurate. As a large portion of the human proteome, for example, is not structurally resolved, extending these calculations to homology models based on related proteins would greatly expand their applicability. We want to see how well predicted G values from homology models match crystal structures in this study. For homology modeling across a wide range of sequence identities, we specifically selected four proteins with a large number of experimentally tested Gs and templates and tested three methods for G calculations. As long as the sequence identity of the model template to the target protein is at least 40%, we find that G-values predicted from homology models perform similarly to those predicted from experimentally established crystal structures. The Rosetta Cartesian ddg protocol, in particular, is resistant to homology modeling's minor structure perturbations. Using Gs to classify variants as low or wild-type-like in abundance, we observe a similar trend in an independent evaluation. Overall, our findings demonstrate that stability calculations based on homology models can be used to replace crystal structure-based calculations with a level of precision that is acceptable as long as the model is built on a template that shares at least 40% of the target protein's sequence.

Homology Modeling and Molecular Docking

Schiff bases are well-known for their numerous chemistry and medicinal chemistry applications due to their intriguing hydrogen-bonding properties. The interaction that occurs between the symmetrical Schiff base ligand on bis [4-hydroxy-6-methyl-3-(1E)-N-[2 (ethylamino) ethyl] ethanimidoyl] pyran-2-one]) receptors in neurological, cancer, and bacterial cells. Thickness practical hypothesis (DFT) was utilized to decide the math, reactivity and electronic properties of this ligand. Homology modeling and molecular docking were used to test their biological and medicinal properties, such as their activities against cancer, viruses, bacteria, and the nervous system. DFT revealed that the localization of electrophilic and nucleophilic attack sites is consistent with the mulliken charges, molecular orbitals (HOMO and LUMO), and MEP results. The theoretical study revealed that the ligand had a low kinetic stability and high chemical reactivity. With binding energy values of 7.36 kcal/mol, 6.35 kcal/mol, 6.19 kcal/mol, and 5.58 kcal/mol, respectively, the ligand exhibited good biological activity against leukemia, breast cancer, Alzheimer, and Covid-19, according to the docking study results. The multiple H-bonds and low binding energy and inhibition constant values provide an explanation for these results. One of the neglected diseases that cause significant morbidity and mortality worldwide is schistosomiasis. The main component of microtubules, tubulin, plays a crucial role in helminthes like schistosomes. By binding -tubulin, Benzimidazole represent potential drug candidates. The purpose of the study was to use the crystal structure of O vis aries (Sheep) -tubulin (PDB ID:) to create a homology model for the -tubulin of S. mansoni.3N2G D) as a starting point, various models of -tubulin were created, and two previously reported Benzimidazole derivatives—NBTP-F and NBTP-OH—were docked to the models. The binding results showed that both S. mansoni and S. haematobium were susceptible to the two NBTP derivatives. In addition, three mutant forms of the wild-type S. mansoni-tubulin were produced, and the mutation F185Y appears to slightly enhance ligand binding. S. haematobium -tubulin is highly susceptible to the tested compounds, as demonstrated by dynamics simulation experiments; In addition, NBTPs susceptibility was altered in mutated S. mansoni models, as was the case with S. mansoni. In addition, seven brand-new Benzimidazole derivatives were synthesized and put through molecular docking tests on the S. mansoni-tubulin model binding site, where they were found to interact well with the pocket.

Designing and Screening of Chaperones

Particularly intriguing is a treatment strategy for Parkinson's disease (PD) that uses chaperones to stabilize the Glucocerebrosidase (GCase) enzyme. The wild-type rat is a popular model for PD;nonetheless, the in-silico model to explain the idea of rodent GCase (rGCase)- chaperone connections, components, and underlying soundness is as yet inaccessible. As a result, in order to fill this void, pH-dependent rGCase homology models, in-silico docking and molecular dynamics and in-vitro enzyme kinetics and thermal stability techniques have been developed by us. The homology modeling results showed that less than 90% of rGCase residues were in the preferred regions, indicating that the models were of adequate quality. AMB's interaction with the active site residues TYR 331, TYR 263, GLN 266, and GLU 358 was found to be stronger at neutral pH than at acidic pH in in-silico studies, and AMB's inhibitory activity (IC50) and binding affinity were found to be higher at neutral pH in in vitro studies than a pH that is acidic. The thermal denaturation assay confirmed that AMB enhanced rGCase thermo stability. The homology model we created for rGCase provides a framework for designing and screening chaperones during the early stages of PD drug discovery. The structure of the lysophosphatidic acid receptor 4 (LPA4) has yet to be determined, but it has emerged as a potential therapeutic target for the treatment of a variety of diseases, including cancer and diabetes caused by obesity. A homology model of LPA4 was constructed in this study to investigate the binding mechanism of LPA species and analogs. Following that, molecular dynamics simulations and energy analyses were performed on five selected LPA species and analogs that had structurally distinct phosphate groups, substitutions on the glycerol backbone, and fatty acyl chains docked into the LPA4 model. The aliphatic residues in the vertical cleft of LPA4 may provide a hydrophobic environment for the fatty acyl moiety of LPA species and its analogs, according to the computational findings. In the meantime, the negatively charged hydrophilic head group of LPA species and their analogs and the positively charged residues in the central cavity of LPA4 may engage in ionic interactions. Additionally, a unique rearrangement of the fatty acyl moiety may result from the hydrophilic head group's unique binding mode with the central cavity of the LPA4 in each species. These findings, taken as a whole, may make it easier to comprehend the mechanism by which LPA4 is activated and assist in the creation of specific ligands that can alter its function for therapeutic purposes.