Docking, Interaction Fingerprint, and Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) of Sigma1 Receptor Ligands, Analogs of the Neuroprotective Agent RC-33

Abstract

The human Sigma1 receptor (S1R), which has been identified as a target with an important role in neuropsychological disorders, was first crystallized 3 years ago. Since S1R structure has no relation with another previous crystallized structures, the presence of the new crystal is an important hallmark for the design of agonists and antagonists against this important target. Some years ago, our group identified RC-33, a potent and selective S1R agonist, endowed with neuroprotective properties. In this work, drawing on new structural information, we studied the interactions of RC-33 and its analogs with the S1R binding site by using computational methods such as docking, interaction fingerprints, and receptor-guided alignment three dimensional quantitative structure–activity relationship (3D-QSAR). We found that RC-33 and its analogs adopted similar orientations within S1R binding site, with high similitude with orientations of the crystallized ligands; such information was used for identifying the residues involved in chemical interactions with ligands. Furthermore, the structure-activity relationship of the studied ligands was adequately described considering classical QSAR tests. All relevant aspects of the interactions between the studied compounds and S1R were covered here, through descriptions of orientations, binding interactions, and features that influence differential affinities. In this sense, the present results could be useful in the future design of novel S1R modulators.

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

“…A systematic and detailed analysis of all possible interactions between LasB and the docked NAMdP could be performed by using Interaction Fingerprints (IFPs). Previous studies have demonstrated that IFP analysis is a valuable tool that allowed for a better schematization of protein-ligand interactions [26,29,30].…”

Considerations for Docking of Selective Angiotensin-Converting Enzyme Inhibitors

“…In this section I am focused on identifying the recurrent interactions between ACE domain binding sites and their ligands, and the residues involved in these interactions. Interaction fingerprints (IFPs) is a very effective method for such analysis, with recent successful applications in diverse protein-ligand systems [84][85][86][87]. "Interaction Fingerprints Panel" of Maestro (Maestro 10.2.011, Schrödinger LLC) was used for constructing the IFPs as described in Singh et al [88,89].…”

Involvement of Chaperone Sigma1R in the Anxiolytic Effect of Fabomotizole

“…In turn, their smaller hydrophobic groups (most often, these are various substituents bonded to amine nitrogen) must be located near the Phe107, Trp164, His154, and Ile124 residues (these residues are included in the secondary hydrophobic site, see Figures S8 and S9 ). In general, Sigma1R ligand molecule includes: a large and small hydrophobic parts connected by a spacer (its length and nature may be different), and at least one amino group that is located somewhere in between these parts or near one of them [ 86 ]. It should be noted that structures of NE-100, (+)-pentazocine and fabomotizole molecules correspond to the abovementioned pharmacophore characteristics of Sigma1R ligands (summarized in Figure 5 ).…”

“…A number of receptor grids was generated to define a ligand binding site for subsequent docking analysis. A grid box of 20 × 20 × 20 Å was created for each ‘ligand–receptor’ complex, centered on the center of mass of the ligand in the selected crystal structure, covering the binding site of Sigma1R [ 86 ]. A scaling factor of 1.0 and a partial charge threshold of 0.25 were used during the generation of the grid boxes.…”