@article {162675, title = {Exploration of Natural Products for Targeting IDH1/2 Mutations in Acute Myeloid Leukemia Through Ligand-Based Pharmacophore Screening, Docking, ADME-T, and Molecular Dynamic Simulation Approaches.}, journal = {Bioinform Biol Insights}, volume = {19}, year = {2025}, month = {2025}, pages = {11779322251399077}, abstract = {

BACKGROUND: Mutations in isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are prevalent drivers of acute myeloid leukemia (AML). While targeted therapies exist, resistance can emerge. This study explored the potential of natural products to identify novel dual IDH inhibitors.

METHODS: In silico screening of the COCONUT database was performed using Lipinski{\textquoteright}s Rule of Five. Pharmacophore modeling identified crucial features for IDH binding. Docking simulations with Glide (Schr{\"o}dinger) assessed binding affinity, followed by MM-GBSA calculations for free energy estimation. The most promising candidate underwent ADME/T and toxicity analysis. Finally, molecular dynamics (MD) simulations evaluated the stability of protein-ligand complexes and binding interactions, followed by trajectory analysis using dynamical cross-correlation matrix (DCCM) and principal component analysis (PCA).

RESULTS: Ternstroside D (CNP0166496) emerged as a potential dual inhibitor of IDH1 and IDH2 mutations. Docking and MM-GBSA analyses showed strong affinities with IDH1 (-14.2, -84.45 kcal/mol) and IDH2 (-16.8, -60.73 kcal/mol), exceeding those of reference inhibitors GSK321A (-9.6 kcal/mol) and Enasidenib (-8.9 kcal/mol). Key hydrogen-bond interactions with catalytic residues and stable binding during MD simulations support its dual mechanism. ADME/T predictions indicated drug-like properties and a favorable safety profile, highlighting Ternstroside D as a natural scaffold with superior binding compared with existing IDH inhibitors.

CONCLUSION: This in silico study provides compelling evidence for Ternstroside D (CNP0166496) as a promising dual inhibitor for IDH1 and IDH2 mutations in AML. Furthermore, in vitro and in vivo studies are warranted to validate these findings.

}, issn = {1177-9322}, doi = {10.1177/11779322251399077}, author = {Das, Uddalak and Regati, Dheemanth Reddy and Kumar, Jitendra and Sowdhamini, R} } @article {149369, title = {Computational analysis of human gut microbial prolyl oligopeptidases (POPs) reveal candidate genes as therapeutics for celiac disease.}, journal = {Sci Rep}, volume = {14}, year = {2024}, month = {2024 Aug 23}, pages = {19641}, abstract = {

Celiac disease (CD) is a common autoimmune disorder in which the patients are unable to digest gluten, which is present in foods made up of wheat, barley and rye. Whilst diagnosis happens late in 80\% of the cases, avoidance of such foods appears to be the common solution. Alternative management strategies are required for the patients and their families since CD is also genetically carried over. Probiotic therapeutics and the consumption of appropriate enzymes, such as prolyloligopeptidases (POPs), from gut-friendly bacteria could reduce the disease burden and provide a better lifestyle for CD patients. We have examined around 5000 gut bacterial genomes and identified nearly 4000 non-redundant putative POPs. A select set of 10 gut bacterial POP sequences were subject to three-dimensional modelling, ligand docking and molecular dynamics simulations where stable interactions were observed between the POPs and gluten peptides. Our study provides sequence and structural analysis of potential POP enzymes in gut bacterial genomes, which form a strong basis to offer probiotic solutions to CD patients. In particular, these enzymes could be lead future therapeutics for this disease.

}, keywords = {Bacteria, Celiac Disease, Computational Biology, Gastrointestinal Microbiome, Glutens, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Probiotics, Prolyl Oligopeptidases, Serine Endopeptidases}, issn = {2045-2322}, doi = {10.1038/s41598-024-70079-1}, author = {Nayak, Soumya and Regati, Dheemanth Reddy and Sowdhamini, Ramanathan} }