title: Docking and ADMET prediction of few GSK-3 inhibitors divulges 6-bromoindirubin-3-oxime as a potential inhibitor.
abstract: GSK-3 is a member of cellular kinases with diversified functions such as cellular differentiation, metabolic signaling, neuronal functions and apoptosis. It has been validated as an important therapeutic target in Alzheimer's disease and type 2 diabetes. Few molecules targeting GSK-3 are currently in clinical trials. In this study, we have compared certain docking and computational ADME (Absorption, Distribution, Metabolism, Excretion) parameters of a few GSK-3 targeted ligands (Indirubin, Hymenialdisine, Meridianins, 6-bromoindirubin-3-oxime) against two control molecules (Tideglusib and LY-2090314) to derive and analyze the basic drug-like properties of the test compounds. Docking between the GSK-3 and various ligands was done using AutoDock while ADME parameters were derived from ADMET server PreADMET and admetSAR. Various docked images were retrieved from docking, indicating the docking sites in the target protein. Out of four compounds tested, 6-bromoindirubin-3-oxime (6-BIO) was found as the best docking and ADME parameters, followed by Hymenialdisine (HMD). The LigPlot interaction results show two residues Leu (188) and Thr (138) to be common at the interaction site. The LD50 of 6-BIO is better than one of the control ligands while very similar to the other. Some of the parameters were very similar to the control ligands, thus, making it a suitable candidate among the test ligands. From this in-silico study, we concluded that 6-BIO is a potent drug candidate which could be further tested in vitro and in vivo to establish a drug molecule. Since, 6-BIO is a chemically modified form of the basic molecule Indirubin, we can hypothesize that certain other modified indirubins could be tested as GSK-3 targeted ligands.
authors.affiliation: Department of Biotechnology, National Institute of Technology, Raipur 492010, Chhattisgarh, India.
authors.forename: Chaluveelaveedu Murleedharan
authors.initials: CM
authors.lastname: Nisha
authors.affiliation: Department of Biotechnology, National Institute of Technology, Raipur 492010, Chhattisgarh, India.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Biotechnology, National Institute of Technology, Raipur 492010, Chhattisgarh, India.
authors.forename: Archana
authors.initials: A
authors.lastname: Vimal
authors.affiliation: Department of Biotechnology, National Institute of Technology, Raipur 492010, Chhattisgarh, India.
authors.forename: Bhukya Mounika
authors.initials: BM
authors.lastname: Bai
authors.affiliation: Department of Chemical Engineering, National Institute of Technology, Raipur 492010, Chhattisgarh, India.
authors.forename: Dharm
authors.initials: D
authors.lastname: Pal
authors.affiliation: Department of Biotechnology, National Institute of Technology, Raipur 492010, Chhattisgarh, India. Electronic address: drawanishkr@gmail.com.
authors.forename: Awanish
authors.initials: A
authors.lastname: Kumar
mesh_terms: D001381:Azepines / Q000737:chemistry; D001665:Binding Sites; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000737:chemistry*; D026121:Indole Alkaloids / Q000737:chemistry; D007211:Indoles / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010091:Oximes / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011758:Pyrroles / Q000737:chemistry; D055672:Static Electricity; D013816:Thermodynamics; D013830:Thiadiazoles / Q000737:chemistry
chemical_list: C483321:6-bromoindirubin-3'-oxime; D001381:Azepines; D007004:Hypoglycemic Agents; D026121:Indole Alkaloids; D007211:Indoles; D008024:Ligands; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013830:Thiadiazoles; C560347:meridianin A; C107079:hymenialdisine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C520571:tideglusib; C027185:indirubin
keywords: 6-Bromoindirubin-3-oxime; ADMET; Docking; Drug candidate; GSK-3