The Application of 3D-QSAR Studies for Novel Cannabinoid Ligands Substituted at the C1‘ Position of the Alkyl Side Chain on the Structural Requirements for Binding to Cannabinoid Receptors CB1 and CB2

Abstract

A set of 30 novel Delta8-tetrahydrocannabinol and cannabidiol analogues were subjected to three-dimensional quantitative structure-activity relationship studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. Using a combination of molecular modeling techniques and NMR spectroscopy, the putative bioactive conformation of the most potent cannabinoid (CB) ligand in the training set was determined. This conformer was used as the template and CB1 and CB2 pharmacophore models were developed. These models were fitted with experimental binding data and gave high correlation coefficients. Contour maps of the CB1 and CB2 models of CoMFA and CoMSIA approaches show that steric effects dominantly determine the binding affinities. The CoMFA and CoMSIA analyses based on the binding affinity data of CB ligands at the CB1 and CB2 receptors allowed us to deduce the possible optimal binding positions. This information can be used for the design of new CB analogues with enhanced activity and other tailored properties.

3D-QSAR study of multi-target-directed AchE inhibitors based on autodocking

“…In addition, S configuration has a greater steric hindrance with amino acids, such as GLY117, GLY118, GLY119, and TRP84. So the R configuration is better to combine protein, which is in agreement with the published articles (Durdagi et al, 2007).…”

Application of 3D QSAR CoMFA/CoMSIA and in silico docking studies on novel renin inhibitors against cardiovascular diseases

“…However, in our study, the X-ray structure of renin is known, therefore, QSAR studies are combined with docking results. This combination as it is shown in our previous studies is very effective to produce novel potential drugs [29,30].…”

“…The steric and electrostatic field energies were calculated using the Lennard-Jones and the Coulomb potentials, respectively, with a 1/r distance-dependent dielectric constant in all intersections of a regularly spaced (0.2 nm) grid [30]. An sp 3 carbon atom with a radius of 1.53 Å and a charge of þ1.0 was used as a probe to calculate the steric and electrostatic energies between the probe and the molecules using the Tripos force field [23].…”

“…On the other hand, reducing a to smaller values will result in a probe atom detecting molecular similarity of its neighborhood more globally. The optimal value of a is between 0.2 and 0.4 [22,33].…”

“…The use of Comperative Molecular Field Analysis (CoMFA) and Comperative Molecular Similarity Indices Analysis (CoMSIA) approaches together provide better ability of visualization and interpretation of the obtained correlations in terms of field contributions [22,23]. Pharmacophore models are developed by using the most potent ligand of the training set as template.…”