Molecular Docking and Molecular Dynamics Simulation Studies of Triterpenes from Vernonia patula with the Cannabinoid Type 1 Receptor (original) (raw)
Related papers
Homology models of the cannabinoid CB1 and CB2 receptors. A docking analysis study
European Journal of Medicinal Chemistry, 2005
The 3D models of both CB1 and CB2 human receptors have been established by homology modeling using as template the X-ray structure of bovine Rhodopsin (code pdb: 1F88) a G-protein-coupled receptor (GPCR). A recursive approach comprising sequence alignment and model building was used to build both models, followed by the refinement of non-conserved regions. The cannabinoid system has been studied by means of docking techniques, using the 3D models of both CB1 and CB2 and well known reference inverse agonist/antagonist compounds. An approach based on the flexibility of the structures has been used to model the receptor-ligand complexes. The structural effects of ligand binding were studied and analyzed on the basis of hydrogen bond interactions, and binding energy calculations. Potential interaction sites of the receptor were determined from analysis of the difference accessible surface area (DASA) study of the protein with and without ligand.
Molecules
Cannabinoid receptor ligands are renowned as being therapeutically crucial for treating diverse health disorders. Phenylspirodrimanes are meroterpenoids with unique and varied structural scaffolds, which are mainly reported from the Stachybotrys genus and display an array of bioactivities. In this work, 114 phenylspirodrimanes reported from Stachybotrys chartarum were screened for their CB2 agonistic potential using docking and molecular dynamic simulation studies. Compound 56 revealed the highest docking score (−11.222 kcal/mol) compared to E3R_6KPF (native agonist, gscore value −12.12 kcal/mol). The molecular docking and molecular simulation results suggest that compound 56 binds to the putative binding site in the CB2 receptor with good affinity involving key interacting amino acid residues similar to that of the native ligands, E3R. The molecular interactions displayed π–π stacking with Phe183 and hydrogen bond interactions with Thr114, Leu182, and Ser285. These findings identif...
Molecular Diversity, 2010
When X-ray structure of a ligand-bound receptor is not available, homology models of the protein of interest can be used to obtain the ligand-binding cavities. The steroelectronic properties of these cavities are directly related to the performed molecular model coordinates. Thus, the use of different template structures for homology may result in variation of ligand-binding modes. We have recently reported the MD simulations of a potent CB ligand at bovine rhodopsin-based CB1 and CB2 receptors (Durdagi et al., Bioorg Med Chem 16:7377-7387, 2008). In this present study, a homology modeling study based on the β2-adrenergic receptor for both CB1 and CB2 receptors was performed, and the results were compared with rhodopsin-based models. In addition, the role of membrane bilayers to the adopted conformations of potent AMG3 CB ligand has been analyzed for receptor-free and membrane-associated receptor systems. The performed MD trajectory analysis results have shown that gauche conformations at the terminal segment of the Electronic supplementary material The online version of this article (alkyl side chain of AMG3 are not favored in solution. Different adopting dihedral angles defined between aromatic and dithiolane rings at the active sites of the CB1 and CB2 receptors, which are adapted lead to different alkyl side chain orientations and thus, may give clues to the medicinal chemists to synthesize more selective CB ligands. The binding sites of receptors derived by rhodopsin-based models have been regenerated using the β2-adrenergic based template receptors. The re-obtained models confirmed the ligand-binding pockets that were derived based on rhodopsin.
A Theoretical Structure-Affinity Relationship Study of Some Cannabinoid Derivatives
Journal of the Chilean Chemical Society, 2008
A ZINDO/1 quantum-chemical structure-affinity relationship study with the KPG model is presented for the in vitro interaction of a group of classical, indolederived and aminoalkylindole-derived cannabinoids with CB 1 and CB 2 receptors. From this work the following conclusions are obtained. CB 1 and CB 2 CB 2 receptor affinities are regulated by different mechanisms involving orbital and charge control. Nevertheless CB 1 and CB 2 classical ligands share three common features: a hydrogen bond to a lysine (for CB 1) or serine (for CB 2), a fully aromatic ring and a branched carbon side chain. In the case of indole-derived and aminoalkylindolederived cannabinoids orientation and alignment rules have been defined as a basis for the comparison of noncongeneric molecules. In this way it was possible to associate the location of molecular fragments of these systems with known molecular systems such as classical cannabinoids. For aminoalkylindoles we have proposed the locus with which they bind to a second receptor site that is available to WIN-55212-2 but not to classical cannabinoids. On the basis of our results we propose a new molecule that should help to discriminate between the above two receptor sites.
Current Science
Cannabinoid (CB) receptors belong to the G proteincoupled receptor (GPCR) family and were activated by endogenous, phytogenic and synthetic modulators. The CB receptors are involved in a variety of physiological processes, including appetite, pain sensation, mood, memory, etc. The potency of ligands with receptors provides the path through which the latter show agonist, antagonist, or inverse agonist behaviour. Due to the unavailability of crystal structure of CB type-2 (CB2) receptor, we used multiple template comparative homology modelling algorithms to construct 3D models for the same. We performed docking and molecular dynamics simulation study of four synthetic drugs in both cannabinoid type-1 (CB1) and CB2 receptors. These ligands show agonist activity with the CB2 receptor and activates it completely. The results are compared with the CB1 receptor. Molecular properties of the ligands, including molecular, polar and solvent-accessible surface areas, and intramolecular hydrogen bonds were evaluated using molecular dynamics simulations. Our finding demonstrates that the ligand AM-1221 shows the highest binding affinity (-12.73 k cal/mol), whereas UR-144 shows the lowest (-9.83 k cal/mol) towards the CB2 receptor. These findings should stimulate the design of ligands with distinct pharmacological properties associated with the CB2 receptor.
Phytotherapy Research, 2020
When tested in the acetic acid-induced writhing and formalin-induced paw-licking tests, the ethanol extract of Vernonia patula (VP) aerial parts showed significant antinociceptive activity. In neuropharmacological tests, it also significantly delayed the onset of sleep, increased the duration of sleeping time, and significantly reduced the locomotor activity and exploratory behaviour of mice. Five phenolic compounds, namely gallic acid, vanillic acid, caffeic acid, quercetin and kaempferol, were detected in VP following HPLC-DAD analysis. The presence of these phenolic compounds in VP provides some support for the observed antinociceptive and sedative effects. A computational study was performed to predict the binding affinity of gallic acid, vanillic acid, caffeic acid, quercetin and kaempferol towards the cannabinoid type 1 (CB1) receptor. Caffeic and vanillic acid showed the highest probable ligand efficiency indices towards the CB1 target. Vanillic acid displayed the best blood-brain barrier penetration prediction score. These findings provide some evidence for the traditional use of VP to treat pain. K E Y W O R D S antinociceptive activity, cannabinoid receptor 1 (CB1), molecular docking, Vernonia patula 1 | INTRODUCTION Vernonia patula (Dryand.) Merr. (Asteraceae), also known as purple fleabane, is an annual weed widely distributed throughout Bangladesh. The plant is used traditionally as an aphrodisiac, and for malaria, respiratory tract disorders, colds, fevers and convulsions (Khare, 2007; Mollik et al., 2010). The leaves are reputed to be beneficial in treating pain (Jahan et al., 2015). Previous chemical studies of the aerial parts of V. patula have revealed the presence of phenolic compounds, flavonoids and terpenoids (Herrera, Chanco, &
2022
Cannabinoid receptors type 2 (CB2R) is a member of class A G protein-coupled receptor (GPCRs) family and a component of the endocannabinoid system modulated by a psychoactive chemical from Cannabis sativa, partial agonist Δ9-tetrahydrocannabinol (Δ9-THC). Selective activation of CB2R allows for the treatment of inflammatory and immune-related conditions without the psychotropic effects of CB1R. While CB2R-selective agonists are available, CB2R partial agonists are scarce. Hence, the pharmacological difference between CB2R full agonist and partial agonist remains to be deciphered, prompting the search for novel partial agonists. Here, using an induced-fit docking approach, we built a partial agonist Δ9-THC bound CB2R system from the inactive CB2R structure (PDB ID: 5ZTY) and performed microsecond molecular dynamics (MD) simulations. The simulations reveal an upward shift of the “toggle switch” W6.48(258) and minor outward movement of the transmembrane helix 6 (TM6). The Dynamics netw...
Journal of Medicinal Chemistry, 2013
Despite the therapeutic promise of the sub-nanomolar affinity cannabinoid CB 2 antagonist, N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan2-yl]-5-(4-chloro-3-methylphenyl)-1-[(4methylphenyl)methyl]-1H-pyrazole-3-carboxamide (SR144528, 1), little is known about its binding site interactions and no primary interaction site for 1 at CB2 has been identified. We report here the results of Glide docking studies in our cannabinoid CB 2 inactive state model that were then tested via compound synthesis, binding and functional assays. Our results show that the amide functional group of 1 is critical to its CB2 affinity and efficacy and that aromatic stacking interactions in the TMH5/6 aromatic cluster of CB2 are also important. Molecular modifications that increased the positive electrostatic potential in the region between the fenchyl and aromatic rings led to more efficacious compounds. This result is consistent with the EC-3 loop negatively charged amino acid, D275 (identified via Glide docking studies) acting as the primary interaction site for 1 and its analogs.
Bioorganic & Medicinal Chemistry Letters, 2007
The combination of NMR spectroscopy and molecular modeling studies provided the putative bioactive conformation for the analgesic cannabinoid (CB) ligand (À)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethylhydroxy-6H-dibenzo[b,d]pyranyl)-2-hexyl 1,3-dithiolane which served as a template in reported three-dimensional quantitative structure-activity relationship (3D QSAR) studies [Durdagi et al., J. Med. Chem. 2007, 50, 2875. The reported 3D models of the CB1 receptor allowed us to construct a new 3D QSAR model based on theoretical calculations and molecular docking studies. Statistical comparison of the constructed two 3D QSAR studies showed the improvement of the new model. In addition, the new model can explain more effectively the experimental data and thus it can serve more efficiently in the rational drug design of pharmacologically optimized CB analogues.