Adamantane-derived scaffolds targeting the sigma-2 receptor; an in vitro and in silico study

Abstract

Novel adamantane-based compounds were synthesized and assessed as potential sigma-2 receptor ligands. Molecular docking and 50 ns molecular dynamic simulation were carried out to determine the binding modes, mechanism of interaction, and stability of these compounds within the active site of the sigma-2 receptor. In addition, the ADME-T properties have been explored. The cytotoxicity in cancer cell lines that express sigma-2 receptors was also examined. In addition, the in silico and cytotoxicity data for the new compounds were compared to a reference sigma-2 receptor ligand with high receptor-binding affinity and selectivity. The data suggests that the new compounds interact with the sigma-2 receptor in a comparable manner to the reference compound, and that adamantane can be used as a scaffold to synthesize sigma-2 receptor ligands with useful functional groups that can be used to conjugate moieties for tumor-imaging or cytotoxic cargo delivery.

Nascent pharmacological advancement in adamantane derivatives

“…[33] As in the case of molecular hybridization, in which one pharmacophore is attached to another one(s) with a probability of increasing biological activity, [34,35] adding an adamantane unit completely modifies the absorption distribution, metabolism and excretion properties of the resultant hybrid molecule. [36] As reported in the literature, the above properties help improve some known leads for pharmacokinetic and pharmacodynamic properties.…”

“…[ 33 ] As in the case of molecular hybridization, in which one pharmacophore is attached to another one(s) with a probability of increasing biological activity, [ 34,35 ] adding an adamantane unit completely modifies the absorption distribution, metabolism and excretion properties of the resultant hybrid molecule. [ 36 ] As reported in the literature, the above properties help improve some known leads for pharmacokinetic and pharmacodynamic properties. Adamantane‐based compounds are reported to possess a plethora of biological activities including antiviral, [ 37,38 ] anticancer, [ 39 ] antimalarial, [ 40 ] antimicrobial, [ 41 ] and inhibitors of various enzymes.…”

Anti-Diabetic Activity of Bioactive Compound Extracted from Spondias mangifera Fruit: In-Vitro and Molecular Docking Approaches

“…These residues are believed to be essential for pancreatic alpha production. alpha-amylase association [34].…”

“…GROMACS 2018.1 package systems were used to run the MD simulations for the top docked poses of the standard molecule, acarbose, and a-sitosterol complexes with pancreatic alpha-amylase (PDB ID: 3BAJ) using the OPLS-AA all-atom force field and the TIP3P water model, as described earlier [34]. In summary, topological parameters for simulated ligands were generated using the SwissParam web service (https://www.swissparam.ch/ (accessed on 10 February 2022) [35].…”