ABSTRACT
BACKGROUND: The N-methyl-D-aspartate (NMDA) receptors are glutamate receptors that play vital roles in central nervous system development and are involved in synaptic plasticity, which is an essential process for learning and memory. The subunit N-methyl D-aspartate receptor subtype 2B (NR2B) is the chief excitatory neurotransmitter receptor in the mammalian brain. Disturbances in the neurotransmission mediated by the NMDA receptor are caused by its overexposure to glutamate neurotransmitter and can be treated by its binding to an antagonist. Among several antagonists, conantokins from cone snails are reported to bind to NMDA receptors. METHODS: This study was designed to analyze the binding mode of conantokins with NMDA receptors in both humans and rats. To study interactions, dockings were performed using AutoDock 4.2 and their results were further analyzed using various computational tools. RESULTS: Detailed analyses revealed that these ligands can bind to active site residues of both receptors as reported in previous studies. CONCLUSIONS: In light of the present results, we suggest that these conantokins can act as antagonists of those receptors and play an important role in understanding the importance of inhibition of NMDA receptors for treatment of Alzheimer's disease.
ABSTRACT
Typhoid presents a major health concern in developing countries with an estimated annual infection rate of 21 million. The disease is caused by Salmonella typhi, a pathogenic bacterium acquiring multiple drug resistance. We aim to identify proteins that could prove to be putative drug targets in the genome of S. typhi str. Ty2. We employed comparative and subtractive genomics to identify targets that are absent in humans and are essential to S. typhi Ty2. We concluded that 46 proteins essential to pathogen are absent in the host genome. Filtration on the basis of drug target prioritization singled out 20 potentially therapeutic targets. Their absence in the host and specificity to S. typhi Ty2 makes them ideal targets for treating typhoid in Homo sapiens. 3D structures of two of the final target enzymes, MurA and MurB have been predicted via homology modeling which are then used for a docking study.
Subject(s)
Anti-Bacterial Agents/pharmacology , Genome, Bacterial , Salmonella typhi/drug effects , Alkyl and Aryl Transferases/chemistry , Alkyl and Aryl Transferases/drug effects , Alkyl and Aryl Transferases/metabolism , Amino Acid Sequence , Host-Pathogen Interactions , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Sequence Data , Salmonella typhi/enzymology , Salmonella typhi/genetics , Sequence Homology, Amino AcidABSTRACT
Muscarinic acetylcholine receptors are stimulated by the neurotransmitter acetylcholine and are involved in various functions across the human body. These receptors have surfaced for their potential use as targets in treatment of Alzheimer's disease. Muscarinic receptors have been reported to show binding interaction with various mamba toxins, such as dendrotoxins and muscarinic toxins that act as antagonists of these receptors. Therefore, in our study we have focused on the binding analysis of these mamba toxins with the M4 and M2 muscarinic acetylcholine autoreceptors for their potential use as targets in treating cognitive symptoms associated with Alzheimer's disease. A ligand dataset was developed that consisted of dendrotoxins and muscarinic toxins originating from various mamba species. Receptor dataset consisted of M4 and M2 muscarinic acetylcholine autoreceptors. Docking studies were performed using AutoDock 4.2 between these ligands with each receptor and further analysis was done using various computational tools. Docking experiments were performed and analyzed to check the binding compatibilities between mamba toxins and muscarinic acetylcholine autoreceptors. Detail analysis revealed that these ligands bind to active site residues of both receptors. Therefore by these in silico results, we suggest that the mamba toxins can be potential antagonists of the M4 and M2 muscarinic acetylcholine autoreceptors.
Subject(s)
Alzheimer Disease/drug therapy , Elapid Venoms/pharmacology , Muscarinic Antagonists/pharmacology , Receptor, Muscarinic M2/antagonists & inhibitors , Receptor, Muscarinic M4/antagonists & inhibitors , Amino Acid Sequence , Binding Sites , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Molecular Docking Simulation , Molecular Sequence Data , Receptor, Muscarinic M2/chemistry , Receptor, Muscarinic M2/genetics , Receptor, Muscarinic M4/chemistry , Receptor, Muscarinic M4/genetics , Sequence AlignmentABSTRACT
Acetylcholinesterases (AChE) are enzymes that function in hydrolyzing the neurotransmitter acetylcholine. Diminished levels of acetylcholine have been reported for various neurodegenerative diseases, especially Alzheimer's. Therefore, acetylcholinesterase inhibitors are being considered quite effective in treating these diseases. Fasciculin 2 is a toxin isolated from Eastern green mamba that had been reported as a reversible acetylcholinesterase inhibitor. In this study, we have reported the in silico analysis of venom toxins via various computational tools used for drug designing, to find out the protein-protein interaction of these toxins in complex with acetylcholinesterase enzyme. In total 15 toxins have been selected from the venoms of various species as ligand dataset, to study their binding interactions with the acetylcholinesterase enzyme.
