Ligand-based Pharmacophore Modeling, Molecular Docking and Simulation Studies for the Exploration of Natural Potent Antiangiogenic Inhibitors Targeting Heat Shock Protein 90

Background: HSP90, a critical molecular chaperone, has become a promising molecular target to be involved in multiple signaling pathways of tumor progression and metastasis. Objective: This study intends to find a novel phytolead targeting HSP90. Methods: In this scenario, we employed an in silico combinatorial approach incorporating 3D-QSAR, pharmacophore generation, pharmacokinetics, docking, MD simulation and metabolism studies. Results: To find a natural novel compound targeting HSP90, a ligand-based pharmacophore model was developed, exploiting 17 diversely classified training set molecules with known experimental activity exhausting the pharmacophore generation (HypoGen algorithm) module of Discovery Studio. The bestdeveloped hypothesis (Hypo1) was employed against the UNPD database to screen lead compounds targeting HSP90. Pterodontoside G (Asteraceae family)became a potent compound with the fit value of 8.80 and an estimated activity of 3.28 nM. Pterodontoside G was taken forward for analog design and pharmacokinetics studies, followed by docking and MD simulation studies. UNPD1 came out to be the best analog following all pharmacokinetics properties with the highest binding energy in comparison with the parent compound and the standard drug (Ganetespib). It mapped all the features of Hypo1 with a fit value of 8.68 and an estimated activity of 4.314 nM, exhibiting greater binding stability inside the active site of HSP90 causing no conformational changes in the protein-ligand complex during MD analysis. Conclusion: The result was further supported by PASS analysis and xenosite reactivity data proposing UNPD1 to hold potent antiangiogenic potential targeting HSP90.