In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer’s disease

Satarker, Sairaj and Maity, Swastika and Mudgal, Jayesh and Nampoothiri, Madhavan (2022) In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer’s disease. Molecular Diversity, 26 (1). pp. 443-466. ISSN 1381-1991

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Abstract

Neuroinflammation is one of the detrimental factors leading to neurodegeneration in Alzheimer’s disease (AD) and other neurodegenerative disorders. The activation of microglial neurokinin 1 receptor (NK1R) by substance P (SP) enhances neuroinflammation which is mediated through pro-inflammatory pathways involving NFkB, ERK1/2, and P38 and thus projects the scope and importance of NK1R inhibitors. Emphasizing the inhibitory role of N Acetyl l Tryptophan (l-NAT) on NK1R, this is the first in silico screening of l-NAT mediated NK1R antagonism. In addition, FDA- approved ligands were screened for their potential NK1R antagonism. The l-NAT was docked in XP (Extra Precision) mode while FDA-approved ligands were screened in HTVS (High Throughput Virtual Screening), SP (Standard Precision), and XP mode onto NK1R (PDB:6HLO). The l-NAT and top 3 compounds FDA-approved ligands were subjected to molecular dynamics (MD) studies of 100 ns simulation time. The XP docking of l-NAT, indacaterol, modafinil and alosetron showed good docking scores. Their 100 ns MD showed brief protein–ligand interactions with an acceptable root mean square deviation. The protein–ligand contacts depicted pi-pi stacking, pi-cation, hydrogen bonds, and water bridges with the amino acids necessary for NK1R inhibition. The variable colour band intensities on the protein–ligand contact map indicated their binding strength with amino acids. The molecular mechanics/generalized born surface area (MM-GBSA) scores suggested favourable binding free energy of the complexes. Thus, our study predicted the ability of l-NAT, indacaterol, modafinil, and alosetron as capable NK1R inhibitors that can aid to curb neuroinflammation in conditions of AD which could be further ascertained in subsequent studies.

Item Type: Article
Uncontrolled Keywords: Alzheimer’s disease; substance P; neurokinin 1 receptor; molecular dynamics; MM-GBSA; l-NAT.
Subjects: Pharmacy > MCOPS Manipal > Pharmacology
Depositing User: KMC Library
Date Deposited: 06 Jun 2022 12:28
Last Modified: 06 Jun 2022 12:28
URI: http://eprints.manipal.edu/id/eprint/158780

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