TY - JOUR
T1 - Binding of SEP-363856 within TAAR1 and the 5HT1A receptor
T2 - implications for the design of novel antipsychotic drugs
AU - Nair, Pramod C.
AU - Miners, John O.
AU - McKinnon, Ross A.
AU - Langmead, Christopher J.
AU - Gregory, Karen J.
AU - Copolov, David
AU - Chan, Sherry Kit Wa
AU - Bastiampillai, Tarun
PY - 2022/1
Y1 - 2022/1
N2 - Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairment. Moreover, newer ‘atypical’ antipsychotic drugs also have significant metabolic adverse-effects. The recent positive clinical trial of the novel drug candidate SEP-363856, which targets non-dopamine receptors (trace amine-associated receptor and the 5HT1A receptor), is a potentially promising development for the management of schizophrenia. In this perspective, we briefly overview the role of TAAR1 and the 5HT1A receptor in schizophrenia and explore the specific binding characteristics of SEP-363856 at these receptors. Molecular dynamics simulations (MDS) indicate that SEP-363856 interacts with a small, common set of conserved residues within the TAAR1 and 5HT1A ligand-binding domain. The primary interaction of SEP-363856 involves binding to the negatively charged aspartate residue (Asp1033.32, TAAR1; Asp1163.32, 5HT1A). In general, the binding of SEP-363856 within TAAR1 involves a greater number of aromatic contacts compared to 5HT1A. MDS provides important insights into the molecular basis of binding site interactions of SEP-363856 with TAAR1 and the 5HT1A receptor, which will be beneficial for understanding the pharmacological uniqueness of SEP-363856 and for the design of novel drug candidates for these newly targeted receptors in the treatment of schizophrenia and related disorders.
AB - Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairment. Moreover, newer ‘atypical’ antipsychotic drugs also have significant metabolic adverse-effects. The recent positive clinical trial of the novel drug candidate SEP-363856, which targets non-dopamine receptors (trace amine-associated receptor and the 5HT1A receptor), is a potentially promising development for the management of schizophrenia. In this perspective, we briefly overview the role of TAAR1 and the 5HT1A receptor in schizophrenia and explore the specific binding characteristics of SEP-363856 at these receptors. Molecular dynamics simulations (MDS) indicate that SEP-363856 interacts with a small, common set of conserved residues within the TAAR1 and 5HT1A ligand-binding domain. The primary interaction of SEP-363856 involves binding to the negatively charged aspartate residue (Asp1033.32, TAAR1; Asp1163.32, 5HT1A). In general, the binding of SEP-363856 within TAAR1 involves a greater number of aromatic contacts compared to 5HT1A. MDS provides important insights into the molecular basis of binding site interactions of SEP-363856 with TAAR1 and the 5HT1A receptor, which will be beneficial for understanding the pharmacological uniqueness of SEP-363856 and for the design of novel drug candidates for these newly targeted receptors in the treatment of schizophrenia and related disorders.
KW - SEP-363856
KW - TAAR1
KW - 5HT1A receptor
KW - antipsychotic drugs
KW - schizophrenia
KW - dopaminergic neurotransmission
UR - http://www.scopus.com/inward/record.url?scp=85112274547&partnerID=8YFLogxK
U2 - 10.1038/s41380-021-01250-7
DO - 10.1038/s41380-021-01250-7
M3 - Review article
AN - SCOPUS:85112274547
SN - 1359-4184
VL - 27
SP - 88
EP - 94
JO - MOLECULAR PSYCHIATRY
JF - MOLECULAR PSYCHIATRY
IS - 1
ER -