3D-QSAR, design, docking and in silico ADME studies of indole-glyoxylamides and indolyl oxoacetamides as potential pancreatic lipase inhibitors

The versatility of indole heterocyclic led to the understanding of their structural requirements to develop new potential derivatives. The indole derivatives estimated to be active against pancreatic lipase have been chosen to develop 3D-QSAR field and atom-based models, validated using the Schrodinger suite. Designing of new agents through QSAR based predictions and performing docking on these compounds helped in defining the binding pattern and pharmacophoric features like π–π stacking interactions, hydrogen bonding, and π-cation interactions with the amino acid residues. The protein-ligand complex displayed good binding energies. In silico ADMET properties have been generated using the Quick-prop module of the Schrodinger suite. The 3D-QSAR model is found to be statistically significant and evaluated using various parameters like R2, R2CV, stability, F-value, P-value, RMSE, Q2, and Pearson-r by PLS factor of 4. The field fractions and contour maps along with their visualizations have helped in inferring the essential nature and type of substituent that should be incorporated for a compound to display potent pancreatic lipase inhibitory activity. These deductions and evaluations of the synthesized compounds through the generation of models could be further utilized for designing new molecules rationally

3D-QSAR, design, docking and in silico ADME studies of indole-glyoxylamides and indolyl oxoacetamides as potential pancreatic lipase inhibitors

284-297The versatility of indole heterocyclic led to the understanding of their structural requirements to develop new potential derivatives. The indole derivatives estimated to be active against pancreatic lipase have been chosen to develop 3D-QSAR field and atom-based models, validated using the Schrodinger suite. Designing of new agents through QSAR based predictions and performing docking on these compounds helped in defining the binding pattern and pharmacophoric features like π–π stacking interactions, hydrogen bonding, and π-cation interactions with the amino acid residues. The protein-ligand complex displayed good binding energies. In silico ADMET properties have been generated using the Quick-prop module of the Schrodinger suite. The 3D-QSAR model is found to be statistically significant and evaluated using various parameters like R2, R2CV, stability, F-value, P-value, RMSE, Q2, and Pearson-r by PLS factor of 4. The field fractions and contour maps along with their visualizations have helped in inferring the essential nature and type of substituent that should be incorporated for a compound to display potent pancreatic lipase inhibitory activity. These deductions and evaluations of the synthesized compounds through the generation of models could be further utilized for designing new molecules rationally

Therapeutic Approaches to Amyotrophic Lateral Sclerosis from the Lab to the Clinic

Amyotrophic Lateral Sclerosis (ALS) is a terminal neuro-degenerative disorder that is clinically recognized as a gradual degeneration of the upper and lower motor neurons, with an average duration of 3 to 5 years from initial of symptoms to death. The mechanisms underlying the pathogenesis and progression of the disease are multifactorial. Therefore, to find effective treatments, it is necessary to understand the heterogeneity underlying the progression of ALS. Recent developments in gene therapy have opened a new avenue to treat this condition, especially for the characterized genetic types. Gene therapy methods have been studied in various pre-clinical settings and clinical trials, and they may be a promising path for developing an effective and safe ALS cure. A growing body of evidence demonstrates abnormalities in metabolic energy at the cellular and whole-body level in animal models and people living with ALS. Using and incorporatig high-throughput "omics" methods have radically transformed our thoughts about ALS, strengthened our understanding of the disease's dynamic molecular architecture, differentiated distinct patient subtypes, and created a reasonable basis for identifying biomarkers and novel individualised treatments. Future clinical and laboratory trials would also focus on the diverse relationships between metabolism and ALS to address the issue of whether targeting poor metabolism in ALS is an effective way to change disease progression. In this review, we focus on the detailed pathogenesis of ALS and highlight principal genes, i.e., SOD1, TDP-43, C9orf72, and FUS, as well as targeted ALS therapies. An attempt is made to provide up-to-date clinical outcomes, including various biomarkers that are thought to be important players in early ALS detection