Abstract
Schizophrenia (SCZ) is one of the brain disorders which affects the thinking and behavioral skills of patients. This disorder comes along with an overproduction of kynurenic acid in the cerebrospinal fluid and the prefrontal cortex of SCZ patients. In this study, marine bacterial compounds were screened for their suitability as antagonists against human kynurenine aminotransferase (hKAT-1) which causes the synthesis of kynurenic acid downstream which ultimately causes the SCZ disorder according to the kynurenic hypothesis of SCZ. The marine actinobacterial compound bonactin shows more promising results than other tested marine compounds such as the histamine H2 blocker famotidine and indole-3-acetic acid (IAC) from docking and in silico toxicological studies carried out here. The obtained results of the Grid-based Ligand Docking with Energetics (Glide) scores of extra-precision (XP) Glide against the target protein hKAT-1 on IAC, famotidine, and bonactin were − 6.581, − 6.500 and − 7.730 kcal/mol where Glide energies were − 29.84, − 28.391, and − 47.565 kcal/mol, respectively. Bonactin is known as an antibacterial and antifungal compound being extracted from a marine Streptomyces sp. Comparing tested compounds against the drug target hKAT-1, bonactin alone showed the best Glide score and Glide energy on the target protein hKAT-1.
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Abbreviations
- IAC :
-
indole-3-acetic acid
- XP :
-
extra-precision
- hKAT :
-
human kynurenine aminotransferase
- kcal/mol :
-
kilocalories/mole
- Glide :
-
grid-based ligand docking with energetics; GEMODEL/GEVDW (depending on authors)
- RBA :
-
relative binding affinity
- IMN :
-
Istituto Mario Negri
- SCZ :
-
schizophrenia
- CNS :
-
central nervous system
- KYNA :
-
kynurenic acid
- CSF :
-
cerebrospinal fluid
- BBB :
-
blood–brain barrier
- AIDS :
-
acquired immune deficiency syndrome
- SP :
-
standard precision
- HTVS :
-
high-throughput virtual screening
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Acknowledgements
The authors thank the University Informatics Centre (UIC), High Performance Computing Facility (HPC) and Bharathidasan University, India, DST-PURSE (Grant No. SR/FT/LS-113/2009), for providing the Schrödinger software access. One of the authors, Muthukumar Krishnan, wishes to thank the Department of Science and Technology, Science Engineering Research Board (DST-SERB), New Delhi, India for awarding the National Postdoctoral fellowship (PDF/2017/002213) and the Director, National Institute of Technology (NIT), Tiruchirappalli – 620 015, Tamil Nadu, India.
Funding
The study was supported by the Bharathidasan University, India, DST-PURSE (Grant No. SR/FT/LS-113/2009). H.-U. Dahms was supported by a grant from the Research Center of Environmental Medicine, Kaohsiung Medical University (KMU), Taiwan (R-1053011).
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Fig S1
Crystal Structure of Human Kynurenine Aminotransferase I in the complex with Indole-3-acetic Acid (PDB ID-3FVU). Snapshot taken by using NGL 3D viewer. (PNG 1695 kb)
Fig S2
Molecular structures of chemicals. (a) IAC, (b) famotidine and (c) bonactin. ChemDraw was used to draw the chemical structures, available from http://scistore.cambridgesoft.com/. (PNG 180 kb)
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Thiyagarajamoorthy, D.K., Arulanandam, C.D., Dahms, HU. et al. Marine Bacterial Compounds Evaluated by In Silico Studies as Antipsychotic Drugs Against Schizophrenia. Mar Biotechnol 20, 639–653 (2018). https://doi.org/10.1007/s10126-018-9835-3
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DOI: https://doi.org/10.1007/s10126-018-9835-3