Computer-Aided Drug Design Against Dopamine D2 Receptor …
107
4 Conclusion
This project was designed with the aim of developing therapeutic compounds (chemical and protein based) for the treatment of Schizophrenia by (i) modification of the
chemical structure of Eticlopride using Bioisosterism and QSAR-based methods and
(ii) mutation of the wild type human NCS1 protein using computational mutational
sensitivity analysis and in silico drug design techniques in both cases. The ultimate
conclusions of this research centred around designing more therapeutically potent
lead compounds than Eticlopride in the small molecule antagonist category as well
as mutated forms of NCS1 wild type that computationally have more stable binding
energetics than wild type NCS1 thereby indicative of being usable for further lead
development/optimization for the treatment of positive symptoms of schizophrenia
like antipsychotic effects.
References
Ajinkya SA, Jadhav P R, Rajamani S (2015) Which is a more debilitating disorder schizophrenia
or dysthymia?—a comparative study. J Clin Diagn Res JCDR 9(5):VC01–VC03. https://doi.org/
10.7860/JCDR/2015/11935.5926
Brisch R, Saniotis A, Wolf R et al (2014) The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Front Psychiatry 5:47.
https://doi.org/10.3389/fpsyt.2014.00047
Carbon M, Kane JM, Leucht S et al (2018) Tardive dyskinesia risk with first- and second-generation
antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry:
Official J World Psychiatric Assoc (WPA) 17(3):330–340. https://doi.org/10.1002/wps.20579
Dong J, Wang NN, Yao ZJ et al (2018) ADMETlab: a platform for systematic ADMET evaluation
based on a comprehensively collected ADMET database J Cheminformatics 10(1):29. https://
doi.org/10.1186/s13321-018-0283-x
Erijman A, Rosenthal E, Shifman JM (2014) How structure defines affinity in protein-protein
interactions. PLoS ONE 9(10):e110085. https://doi.org/10.1371/journal.pone.0110085
Kabbani N, Woll MP, Nordman JC et al (2012) Dopamine receptor interacting proteins: targeting
neuronal calcium sensor-1/D2 dopamine receptor interaction for ANtipsychotic Drug Devel. Curr
Drug Targets 13(1):72–79. https://doi.org/10.2174/138945012798868515
Li P, Snyder GL, Vanover KE (2016) Dopamine Targeting Drugs for the Treatment of Schizophrenia:
Past, Present and Future. Curr Top Med Chem 16(29):3385–3403. https://doi.org/10.2174/156
8026616666160608084834
Makhouri FR, Ghasemi JB (2018) In silico studies in drug research against neurodegenerative
diseases. Curr Neuropharmacol 16(6):664–725. https://doi.org/10.2174/1570159X1566617082
3095628
Pajouhesh H, Lenz GR (2005) Medicinal chemical properties of successful central nervous system
drugs. NeuroRx 2:541–553. https://doi.org/10.1602/neurorx.2.4.541
Patel KR, Cherian J, Gohil K et al (2014) Schizophrenia: overview and treatment options. P & T:
A peer-Rev J formulary Manage 39(9):638–645
107
4 Conclusion
This project was designed with the aim of developing therapeutic compounds (chemical and protein based) for the treatment of Schizophrenia by (i) modification of the
chemical structure of Eticlopride using Bioisosterism and QSAR-based methods and
(ii) mutation of the wild type human NCS1 protein using computational mutational
sensitivity analysis and in silico drug design techniques in both cases. The ultimate
conclusions of this research centred around designing more therapeutically potent
lead compounds than Eticlopride in the small molecule antagonist category as well
as mutated forms of NCS1 wild type that computationally have more stable binding
energetics than wild type NCS1 thereby indicative of being usable for further lead
development/optimization for the treatment of positive symptoms of schizophrenia
like antipsychotic effects.
References
Ajinkya SA, Jadhav P R, Rajamani S (2015) Which is a more debilitating disorder schizophrenia
or dysthymia?—a comparative study. J Clin Diagn Res JCDR 9(5):VC01–VC03. https://doi.org/
10.7860/JCDR/2015/11935.5926
Brisch R, Saniotis A, Wolf R et al (2014) The role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue. Front Psychiatry 5:47.
https://doi.org/10.3389/fpsyt.2014.00047
Carbon M, Kane JM, Leucht S et al (2018) Tardive dyskinesia risk with first- and second-generation
antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry:
Official J World Psychiatric Assoc (WPA) 17(3):330–340. https://doi.org/10.1002/wps.20579
Dong J, Wang NN, Yao ZJ et al (2018) ADMETlab: a platform for systematic ADMET evaluation
based on a comprehensively collected ADMET database J Cheminformatics 10(1):29. https://
doi.org/10.1186/s13321-018-0283-x
Erijman A, Rosenthal E, Shifman JM (2014) How structure defines affinity in protein-protein
interactions. PLoS ONE 9(10):e110085. https://doi.org/10.1371/journal.pone.0110085
Kabbani N, Woll MP, Nordman JC et al (2012) Dopamine receptor interacting proteins: targeting
neuronal calcium sensor-1/D2 dopamine receptor interaction for ANtipsychotic Drug Devel. Curr
Drug Targets 13(1):72–79. https://doi.org/10.2174/138945012798868515
Li P, Snyder GL, Vanover KE (2016) Dopamine Targeting Drugs for the Treatment of Schizophrenia:
Past, Present and Future. Curr Top Med Chem 16(29):3385–3403. https://doi.org/10.2174/156
8026616666160608084834
Makhouri FR, Ghasemi JB (2018) In silico studies in drug research against neurodegenerative
diseases. Curr Neuropharmacol 16(6):664–725. https://doi.org/10.2174/1570159X1566617082
3095628
Pajouhesh H, Lenz GR (2005) Medicinal chemical properties of successful central nervous system
drugs. NeuroRx 2:541–553. https://doi.org/10.1602/neurorx.2.4.541
Patel KR, Cherian J, Gohil K et al (2014) Schizophrenia: overview and treatment options. P & T:
A peer-Rev J formulary Manage 39(9):638–645