Insights into the Interactions between Maleimide Derivates and GSK3β Combining Molecular Docking and QSAR

Abstract

Many protein kinase (PK) inhibitors have been reported in recent years, but only a few have been approved for clinical use. The understanding of the available molecular information using computational tools is an alternative to contribute to this process. With this in mind, we studied the binding modes of 77 maleimide derivates inside the PK glycogen synthase kinase 3 beta (GSK3β) using docking experiments. We found that the orientations that these compounds adopt inside GSK3β binding site prioritize the formation of hydrogen bond (HB) interactions between the maleimide group and the residues at the hinge region (residues Val135 and Asp133), and adopt propeller-like conformations (where the maleimide is the propeller axis and the heterocyclic substituents are two slanted blades). In addition, quantitative structure–activity relationship (QSAR) models using CoMSIA methodology were constructed to explain the trend of the GSK3β inhibitory activities for the studied compounds. We found a model to explain the structure–activity relationship of non-cyclic maleimide (NCM) derivatives (54 compounds). The best CoMSIA model (training set included 44 compounds) included steric, hydrophobic, and HB donor fields and had a good Q2 value of 0.539. It also predicted adequately the most active compounds contained in the test set. Furthermore, the analysis of the plots of the steric CoMSIA field describes the elements involved in the differential potency of the inhibitors that can be considered for the selection of suitable inhibitors.

Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?

“…Docking tests were performed using the software Glide [ 12 ] and Autodock Vina [ 60 ]. Glide offers a complete solution for ligand–receptor docking and is widely used for drug discovery [ 83 , 84 ], virtual screening [ 85 , 86 ], structure-activity relationship analysis [ 87 , 88 , 89 ], pharmacophore modeling [ 90 , 91 , 92 ], evaluation of enzymatic reaction pathways [ 93 , 94 ], and other studies. All grid boxes for molecular docking were centered in the ligand position coming from the crystal structures.…”

Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors

“…These compounds were docked in nACE (PDB codes 6EN5 and 6F9V) and cACE (PDB codes 6F9T and 6F9U) binding sites. Docking was performed with Glide SP and XP methods [94,95], by using the same protocol and parameters that were used by my group in previous works [96][97][98][99], and by including constraints C1 and C2 (or C3). represents the distance between one of the ligand C-terminal carboxylate oxygen atoms (the closest one) and the side chain N of the residue K489/K511 from nACE/cACE.…”

Structural Requirements of N-alpha-Mercaptoacetyl Dipeptide (NAMdP) Inhibitors of Pseudomonas Aeruginosa Virulence Factor LasB: 3D-QSAR, Molecular Docking, and Interaction Fingerprint Studies

“…Standard (SP) and extra-precision (XP) modes were run in Glide [35], but only the XP mode was used to find adequate poses for all ligands [36]. The Glide protocol and parameters were the same as reported in previous reports [37][38][39]. The selection of poses was based on looking for the observed protein-ligand interactions patterns in the reported PDB crystals of LasB, and in the selection of the lowest scoring energy from among the adequate poses.…”