@article {166930, title = {Rational design and comparative docking and simulation of modified FLT3 inhibitors: a study on enhanced binding stability and inhibition potency}, journal = {Journal of Molecular Modeling}, volume = {32}, year = {2026}, month = {05}, abstract = {

Context: FLT3 is a critical therapeutic target for acute myeloid leukemia (AML), and its inhibition remains a key strategy in AML management. In this study, we optimized the known compound CHEMBL4444839 to design a novel analogue, CHEMBL4444839-Analogue, showing improved pharmacological and structural characteristics. Pharmacokinetic profiling evaluation revealed that the analogue had enhanced drug-likeness, metabolic stability, and intestinal permeability, along with reduced predicted toxicity. Molecular docking revealed that CHEMBL4444839-Analogue exhibited a binding energy of -10.4 kcal/mol versus -8.7 kcal/mol for the parent compound, forming additional hydrogen bonds and hydrophobic contacts with GLU661, CYS694, LEU818, and PHE830 in the ATP binding pocket. Molecular dynamics simulation over 100 ns demonstrated lower average RMSD (1.78 {\r A} vs 2.34 {\r A}) and reduced RMSF fluctuations at the activation loop and DFG-out region, indicating enhanced conformational stability. Free energy calculations confirmed higher thermodynamic stability of the analogue versus CHEMBL4444839. The analogue also restricted domain motion and improved residue correlation, indicating better stabilization of FLT3 in its inactive conformation. Incorporation of a fluorocyclobutane moiety significantly contributed to enhanced rigidity and optimized interaction geometry, collectively establishing CHEMBL4444839-Analogue as a more promising and selective FLT3 inhibitor for AML therapy. Methods: Docking of CHEMBL4444839 and its designed analogue was performed to analyze binding interactions and guide structural modifications. Pharmacokinetic and toxicity parameters were predicted using SwissADME, ADMETlab 2.0, and ProTox-II. Molecular dynamics simulations were executed with GROMACS 2023 using the CHARMM36 force field to assess conformational stability, followed by MM-PBSA and dynamic cross-correlation analyses. The integrated computational results demonstrated that CHEMBL4444839-Analogue achieved stronger binding affinity, reduced flexibility, and superior stability compared to the parent molecule, validating its potential as an optimized FLT3 inhibitor candidate for further biochemical and therapeutic evaluation.

}, keywords = {ADMET; Acute myeloid leukemia; FLT3; Molecular docking; Molecular dynamics simulation; Pharmacophore.}, doi = {10.1007/s00894-026-06761-0}, url = {https://pubmed.ncbi.nlm.nih.gov/42144504/}, author = {Das, Uddalak and Regati, Dheemanth and Sowdhamini, R. and Kumar, Jitendra} } @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 {26282, title = {UNC-16/JIP3 regulates early events in synaptic vesicle protein trafficking via LRK-1/LRRK2 and AP complexes.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 Nov 16}, pages = {e1007100}, abstract = {

JIP3/UNC-16/dSYD is a MAPK-scaffolding protein with roles in protein trafficking. We show that it is present on the Golgi and is necessary for the polarized distribution of synaptic vesicle proteins (SVPs) and dendritic proteins in neurons. UNC-16 excludes Golgi enzymes from SVP transport carriers and facilitates inclusion of specific SVPs into the same transport carrier. The SVP trafficking roles of UNC-16 are mediated through LRK-1, whose localization to the Golgi is reduced in unc-16 animals. UNC-16, through LRK-1, also enables Golgi-localization of the μ-subunit of the AP-1 complex. AP1 regulates the size but not the composition of SVP transport carriers. Additionally, UNC-16 and LRK-1 through the AP-3 complex regulates the composition but not the size of the SVP transport carrier. These early biogenesis steps are essential for dependence on the synaptic vesicle motor, UNC-104 for axonal transport. Our results show that UNC-16 and its downstream effectors, LRK-1 and the AP complexes function at the Golgi and/or post-Golgi compartments to control early steps of SV biogenesis. The UNC-16 dependent steps of exclusion, inclusion and motor recruitment are critical for polarized distribution of neuronal cargo.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1007100}, author = {Choudhary, Bikash and Kamak, Madhushree and Ratnakaran, Neena and Kumar, Jitendra and Awasthi, Anjali and Li, Chun and Nguyen, Ken and Matsumoto, Kunihiro and Hisamoto, Naoki and Koushika, Sandhya P} }