Use of molecular modeling, docking, and 3D-QSAR studies for the determination of the binding mode of benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3β inhibitors

Abstract

Molecular modelling and docking studies along with three-dimensional quantitative structure relationships (3D-QSAR) studies have been used to determine the correct binding mode of glycogen synthase kinase 3β (GSK-3β) inhibitors. The approaches of Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) are used for the 3D-QSAR of 51 substituted 3-benzofuranyl-4-indolyl-maleimides as GSK-3β inhibitors. Two binding modes of the inhibitors to the binding site of GSK-3β are investigated. The binding mode 1 yielded better 3D-QSAR correlations using both CoMFA and CoMSIA methodologies. The three-component CoMFA model from the steric and electrostatic fields for the experimentally determined pIC 50 values has the following statistics: R 2 (cv) = 0.386 and SE(cv) = 0.854 for the cross-validation, and R 2 = 0.811 and SE = 0.474 for the fitted correlation. F (3,47) = 67.034, and Probability.of R 2 = 0 (3,47) = 0.000. The binding mode suggested by the results of this study is consistent with the preliminary results of X-ray crystal structures of inhibitor-bound GSK-3β. The 3D-QSAR models were used for the estimation of the inhibitory potency of two additional compounds.

In silico and in vivo based scientific evaluation of traditional anti-diabetic herb Hodgsonia heteroclita

“…In this letter, in an effort to gain first evidence for the antidiabetic activity of the functional food H. heteroclita, we present an in silico docking approach for the identification of compounds inhibiting glycogen synthase kinase3 (GSK-3 ). Examination of 3D structures of GSK-3 from PDB reveals two types of structures based on the presence of Phe67 and Arg141 residue in its active site and can be named as 1R0E and 1Q4L type (Kim et al, 2009). …”

Structure‐Guided Design of a Highly Selective Glycogen Synthase Kinase‐3β Inhibitor: a Superior Neuroprotective Pyrazolone Showing Antimania Effects

“…[15, 16] Both of these compounds are derived from the natural product staurosporine (Figure 1). In further investigations aimed at improving largely target selectivity, we decided to explore the possibility of replacing the 5-membered maleimide core with other heterocyclic systems capable of maintaining the required hydrogen-bonding patterns between the small molecule and enzyme.…”

“…Following this logic, a series of compounds, the 5-membered-ring pyrazolones, was considered as displayed in Figure 2. Employing the original X-ray co-crystal structures, we docked [16] the new pyrazolones to the active site of GSK-3β and observed that the pyrazolone portion of compound 3a provides key hydrogen-bonding interactions with the backbone carbonyl group of Asp 133 (1.90 Å) and the backbone amide of Val 135 (1.65 Å) as shown in Figure 3. The characteristic hydrogen-bonding interaction patterns were maintained for these new compounds.…”

“…In this model, the combination produces an increase in locomotor activity, which is blocked by known mood stabilizers, such as lithium and valproate. [16, 19] Following pretreatment with vehicle, valproate or compound 3a (150 mg kg −1 ), eight-week old C57BL/6J male mice were injected with water, Amph (4 mg kg −1 ) or a mixture of Amph (4 mg kg −1 ) and CDP (2.5 mg kg −1 ) and placed in open field chambers where locomotor activity was monitored for 60 min. Data were analyzed with analysis of variance followed by Fisher’s PLSD post-hoc tests.…”

Role of Ligand-Based Drug Design Methodologies toward the Discovery of New Anti- Alzheimer Agents: Futures Perspectives in Fragment-Based Ligand Design

“…Many studies have been realized for search of new GSK-3β inhibitors by applying LBDD [39,[61][62][63][64][65][66][67][68][69][70]. The most promising work in this area is related with the first computational chemistry mt-QSAR model for anti-AD, antiparasitic, anti-fungi, and anti-bacterial activity of GSK-3 inhibitors [39].…”