102
D. Chaudhuri and P. Bhattacharjee
2015). Research into cause and treatment of schizophrenia proposes a complex
combination of physical, hereditary, mental and ecological components which can
combine to develop the condition. Antipsychotic drugs are the key mode of treatment
for major symptoms of Schizophrenia (Patel et al. 2014). Present antipsychotic drugs
can show tardive dyskinesia as side effects in the patients who consume such drugs
for long period of time (Carbon et al. 2018). Other side effects include irregular
heartbeat and muscle instability.
A hypothesis exists regarding dysregulation of neurotransmitters like dopamine
and over-stimulation of dopamine D2 receptors (D2R) in subcortical and limbic brain
schizophrenia development. This hypothesis is referred as the Dopamine Hypothesis
(Brisch et al. 2014). This hypothesis postulates that the maximum numbers of antipsychotic drugs that are used to treat symptoms of Schizophrenia are antagonists with
respect to targeting the Dopamine D2R (Li et al. 2016). Neuronal calcium sensor-1
(NCS-1) is one of the important members of calcium-myristoyl-switch proteins that
have been known to act as calcium-ion sensors. NCS-1 binds in the signalling site
for synaptic activity and desensitizes the D2 receptors. Since D2-NCS1 interaction
modulates D2 mediated neurotransmission signalling pathway, this interaction has
been chosen as an important focus area for the development of new antipsychotic
drugs (Kabbani et al. 2012). Computer-aided drug design assists in determination
of binding affinity and selectivity of lead candidate binding to the receptor. Aside
from binding affinity determination, computer-aided drug design methodology also
incorporates determination of pharmacokinetic and pharmacodynamics properties
of the lead and uses the techniques of molecular docking and scoring, molecular
diversity and combinatorial chemistry. These techniques reduce the cost of drug
discovery and development as well as reduce the time needed for new, modified
or repurposed lead candidate drug development (Makhouri and Ghasemi 2018). It
has been determined that there is urgent need for the development of more potent
targeted drugs against schizophrenia. This computational drug design project centres
around (i) modification of an existing well-known drug named Eticlopride to yield
analogues with better pharmacological properties and (ii) develop protein-based therapeutic molecules by introducing mutations in the NCS-1 protein with better binding
efficacy and introducing reduce side effects and improving stability of mutant.
2 Materials and Methodology
2.1 Generation of Novel Lead Compounds
Eticlopride is an important antagonist drug with high affinity towards dopamine D2
receptors and used as lead for designing antipsychotic drugs. A shape decoding
tool LigDream was used to derive 100 novel leads had been derived from the
parent compound Eticlopride. SWISSADME and ADMETLab database were used
to estimate physicochemical characteristics of Eticlopride and other newly designed
D. Chaudhuri and P. Bhattacharjee
2015). Research into cause and treatment of schizophrenia proposes a complex
combination of physical, hereditary, mental and ecological components which can
combine to develop the condition. Antipsychotic drugs are the key mode of treatment
for major symptoms of Schizophrenia (Patel et al. 2014). Present antipsychotic drugs
can show tardive dyskinesia as side effects in the patients who consume such drugs
for long period of time (Carbon et al. 2018). Other side effects include irregular
heartbeat and muscle instability.
A hypothesis exists regarding dysregulation of neurotransmitters like dopamine
and over-stimulation of dopamine D2 receptors (D2R) in subcortical and limbic brain
schizophrenia development. This hypothesis is referred as the Dopamine Hypothesis
(Brisch et al. 2014). This hypothesis postulates that the maximum numbers of antipsychotic drugs that are used to treat symptoms of Schizophrenia are antagonists with
respect to targeting the Dopamine D2R (Li et al. 2016). Neuronal calcium sensor-1
(NCS-1) is one of the important members of calcium-myristoyl-switch proteins that
have been known to act as calcium-ion sensors. NCS-1 binds in the signalling site
for synaptic activity and desensitizes the D2 receptors. Since D2-NCS1 interaction
modulates D2 mediated neurotransmission signalling pathway, this interaction has
been chosen as an important focus area for the development of new antipsychotic
drugs (Kabbani et al. 2012). Computer-aided drug design assists in determination
of binding affinity and selectivity of lead candidate binding to the receptor. Aside
from binding affinity determination, computer-aided drug design methodology also
incorporates determination of pharmacokinetic and pharmacodynamics properties
of the lead and uses the techniques of molecular docking and scoring, molecular
diversity and combinatorial chemistry. These techniques reduce the cost of drug
discovery and development as well as reduce the time needed for new, modified
or repurposed lead candidate drug development (Makhouri and Ghasemi 2018). It
has been determined that there is urgent need for the development of more potent
targeted drugs against schizophrenia. This computational drug design project centres
around (i) modification of an existing well-known drug named Eticlopride to yield
analogues with better pharmacological properties and (ii) develop protein-based therapeutic molecules by introducing mutations in the NCS-1 protein with better binding
efficacy and introducing reduce side effects and improving stability of mutant.
2 Materials and Methodology
2.1 Generation of Novel Lead Compounds
Eticlopride is an important antagonist drug with high affinity towards dopamine D2
receptors and used as lead for designing antipsychotic drugs. A shape decoding
tool LigDream was used to derive 100 novel leads had been derived from the
parent compound Eticlopride. SWISSADME and ADMETLab database were used
to estimate physicochemical characteristics of Eticlopride and other newly designed