Computer-Aided Drug Design Against
Dopamine D2 Receptor
for Antischizophrenia Drug Development
Dipankar Chaudhuri and Pradipta Bhattacharjee
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
1 Introduction
Schizophrenia is a complex debilitating psychological ailment that manifests its
symptoms through decades of an afflicted patient’s lifetime. Schizophrenia is considered by medical practitioners and scientists to be a type of psychosis (Ajinkya et al.
D. Chaudhuri (B) · P. Bhattacharjee
Department of Biotechnology, Heritage Institute of Technology, Chowbaga Road P.O, Anandapur,
East Kolkata Township, Kolkata, West Bengal 700107, India
e-mail: dipankar.chaudhuri@heritageit.edu
© Springer Nature Singapore Pte Ltd. 2021
D. Ramkrishna et al. (eds.), Advances in Bioprocess Engineering and Technology,
Lecture Notes in Bioengineering,
https://doi.org/10.1007/978-981-15-7409-2_10
101
Dopamine D2 Receptor
for Antischizophrenia Drug Development
Dipankar Chaudhuri and Pradipta Bhattacharjee
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
1 Introduction
Schizophrenia is a complex debilitating psychological ailment that manifests its
symptoms through decades of an afflicted patient’s lifetime. Schizophrenia is considered by medical practitioners and scientists to be a type of psychosis (Ajinkya et al.
D. Chaudhuri (B) · P. Bhattacharjee
Department of Biotechnology, Heritage Institute of Technology, Chowbaga Road P.O, Anandapur,
East Kolkata Township, Kolkata, West Bengal 700107, India
e-mail: dipankar.chaudhuri@heritageit.edu
© Springer Nature Singapore Pte Ltd. 2021
D. Ramkrishna et al. (eds.), Advances in Bioprocess Engineering and Technology,
Lecture Notes in Bioengineering,
https://doi.org/10.1007/978-981-15-7409-2_10
101