Structure Based Drug Design towards Exploring Potential Anti-Psychotic and Anti-Depressant Activity of Possible Stiff Base of Psilocybin

One among four people in the world are affected by mental or neurological illness at some point of their lives. An estimated number of 450 million people suffers from neurological disorders of one or the other type making mental disorders as the leading cause for disability across the globe. Under psychosis and depression maintenance therapy drug acting on Dopamine (D2) and 5-Hydroxytryptamine receptor (5HT2R) respectively are used in clinical practices. Our study is to design several series of novel chemical entity based on scaffold of psychedelic prodrug i.e. psilocybin. As protein-ligand interactions play a key role in structure based drug design, by using molecular docking, we screened 9 hypothetical inhibitors and investigated their binding affinity against D2 and 5HT2R. We have performed homology modelling to predict 3D structure and build a templet using FASTA sequence of amino acid D2 and 5-HT2 receptor using UniProt database (accession number: P14416 & P28223) and swiss-modeller. In this investigation we performed molecular docking and molecular dynamic study using AutoDock software on their respective grid pocket. Several physicochemical description, pharmacokinetic properties, toxicity, and drug-likeness score with respective 9 hypothetical inhibitors were access using QikProp software, molispiration and OSIRIS property explorer web server. The docking results were evaluated based on free energies of binding (ΔG, kcal/mol) and the results suggested that all the 9 hypothetical chemical entity to be potent inhibitor of D2 and 5HT2R. All the hypothetical inhibitors respect the Lipinski's rule of five. Based on these observations, we firmly believe that the stiff base of psilocybin could aid in efficient anti-psychotic and anti-depressants in drug design.