DAUD MARIAM OMOWUNMI
Nigeria
COMPUTATIONAL MODELLING DESIGN OF NOVEL NMDAR AGONIST FOR THE TREATMENT OF SCHIZOPHRENIA
Mariam Omowunmi Daud1 Amena Khatun Manica2, Michael Olanrewaju Faloyo3, Afuape Raphael Akinwunmi4 Aminat Motunrayo Adekunle5, Aminat Adedolapo Adekola2, Ilyas Adisa Lawal6, Musiliyu Ayofe Salawu7, Jamiu Adewole Muritala8, Ridwan Olajire Muraina2, Rukayat Abiodun Hassan5, Sherif Olabisi Ogunyemi5
1Department of Biochemistry, Ladoke Akintola University of Technology, Oyo State, Nigeria
2Department of Chemistry, University of New Haven, West Haven, CT, USA
3Biomedical Science Department, School of Science, Engineering and Environment, University of Salford, Manchester, United Kingdom
4Department of Biology, College of Science and Technology, North Carolina Agriculture and Technical State University
5Department of Biochemistry, College of Medicine, University of Lagos, Lagos State, Nigeria
6Department of Biochemistry, Lagos State University, Lagos State, Nigeria
7Chemical Sciences Department, Biochemistry and nutrition unit, Fountain University Osun State, Nigeria
8Department of Biochemistry, Kogi State University, Kogi State, Nigeria
Abstract
Background
Schizophrenia (SZ) is a complex, chronic mental disorder characterized by positive symptoms (such as delusions and hallucinations), negative symptoms (including anhedonia, alogia, avolition, and social withdrawal), and cognitive deficits (affecting attention, processing speed, verbal and visuospatial learning, problem-solving, working memory, and mental flexibility). Extensive animal and clinical studies have emphasized the NMDAR hypofunction hypothesis of SZ. Glycine plays a crucial role as an agonist of NMDAR, enhancing the receptors affinity for glutamate and supporting normal synaptic function and plasticity, that is, signal transmission between neurons. In the absence of glycine and two any other co-agonists (serine and D-cycloserine), NMDAR responsiveness to glutamate decreases, reducing its likelihood to open and allow ion flow, which leads to impaired synaptic plasticity and neurotransmission. Current antipsychotic treatments are severely limited, as they only address positive symptoms, can lead to significant neurological and metabolic side effects such as sexual dysfunction, and are effective in only about half of SZ patients. Similarly, direct glycine-site modulators have shown considerable limitations due to high-dose usage, such as nausea, nephrotoxicity, anxiety, depression, and hyperexcitability resulting from the external administration of glycine, serine, and D-cycloserine.
Methods
To this effect, the current study considers glycine-like compounds with improved BBB permeability directly targeting the Glycine modulatory site (GMS). A thorough evaluation encompassing ADMET analysis, virtual screening, and molecular dynamics was used to screen the glycine-like library
Results
Data collected revealed Compound_8, Compound_15, and Compound_945 as promising agonists with lesser toxicity and improved BBB permeability.
Conclusions
Further experimental validation is needed to confirm their preclinical relevance as SZ treatment.
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