Advances Of Bio process Engineering & Technology: Biochemistry Studies

by SAFE SERVICE (Author), Doraiswami Ramkrishna (Author), Subhabrata Sengupta (Author), Sudipta Dey Bandyopadhyay (Author), Avijit Ghosh (Author) 

Abstract:

Schizophrenia is a long term psychosis caused by dysregulation of dopamine D2R. Existing antipsychotic drugs that alleviate positive symptoms of schizophrenia exhibit varied side effects for which designing antipsychotic drugs with reduced side effects remains an important therapeutic goal. This research project has been designed to develop potential amino acid and small molecule-based lead compounds for the reduction of schizophrenic symptoms using in silico drug design tools and methods. Use of LIGDREAM resulted in generation of 100 analogues of Eticlopride. Those with better ADMET properties were subjected to molecular docking against D2R receptor using AutoDock Vina and iGEM dock which yielded two analogues that had more substantial binding affinities for D2R than Eticlopride. NCS-1 is a signalling protein that desensitizes Dopamine D2R. Hence, a protein-based therapeutic compound for schizophrenia was being developed by conserved mutations of two amino acid residues on NCS1 (Phe55 and Leu189) by more hydrophilic and hydrophobic substituent, respectively. Protein-protein docking using the CLUSPRO docking portal and subsequent energy analysis have shown that increased hydrophilicity one had enhanced stabilization. Results obtained from both the modified Eticlopride leads and NCS1 mutations indicate that they can be collectively taken further downstream in anti-schizophrenia drug development.

Keywords:

• Schizophrenia
• D2 receptor
• Eticlopride
• Small molecule-protein docking
• Protein-protein docking