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Abstract Schizophrenia is a chronic neurological disorder in which a person suffers from emotional and intellectual disturbances. First generation antipsychotics for Schizophrenia were replaced with by second generation ones with less side-effects like Parkinsonism and Hyperprolactinemia. A novel, computer-based drug designing technique, has emerged to develop more efficient drugs. One of the computational methods becoming increasingly popular to develop new drugs is relying on Pharmacophores. This method was utilized to develop pharmacophore models of Akt2 inhibitors and β2-Adrenoceptor agonists. A pharmacophore model is proposed, using fourteen second generation and one first generation antipsychotic drugs for Schizophrenia that are effective against both 5-HT2a and D2 receptors.
Hydrogen bond acceptors (HBA), aromatic rings (AR ring) and positive ionizable (PI) groups were identified computationally as pharmacophore features by LigandScout. The distance range calculated by Visual Molecular Dynamics (VMD) between AR-HBA, AR-PI and HBA- PI was 3.68 A°-5.74 A°, 5.66 A°-7.64 A° and 3.77 A°-5.38 A°, respectively. This study should help finding specific and more efficient drugs for Schizophrenia in future.
Key words Pharmacophore, Schizophrenia, 5HT2a, D2, Receptors.
INTRODUCTION Schizophrenia causes emotional disturbances and distorted thought processes. According to World Health Organization (WHO), approximately 24 million people worldwide suffer from this disease (Mueser and Jeste, 2011). In a developing country like Pakistan, it is believed that a schizophrenic patient or someone with any mental disorder is suffering from demonic possessions (Karim et al., 2004). Therefore, owing to the lack of education, the attempts to find a cure from spiritual means is done. However, science explains a wide range of causes of schizophrenia e.g. genetic, environmental, drug abuse, inactive social life and chemical imbalance.
The chemical imbalance of Schizophrenia is due to alterations in the dopamine, serotonin, glutamate and other neurotransmitters pathways in the brain. Dopamine follows four pathways, namely the mesolimbic, mesocortical, nigrostriatal and tuberinfundibular pathways, to perform different functions in brain (Stahl, 2002). Mesolimbic pathway is involved in motivation, emotions, pleasure and reward. The hyperactivity of dopamine in the neurons in Mesolimbic pathway causes the positive symptoms of Schizophrenia. Mesocortical pathway is involved in emotions, executive function and cognition. The hypofunction of dopamine in this pathway leads to negative and cognitive symptoms of Schizophrenia (Lind et al., 2005). Motor planning and movement are the primary functions of nigrostriatal...