Author Correction: Design and Molecular dynamic Investigations of 7,8-Dihydroxyflavone Derivatives as Potential Neuroprotective Agents Against Alpha-synuclein.

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Design and Molecular dynamic Investigations of 7,8-Dihydroxyflavone Derivatives as Potential Neuroprotective Agents Against Alpha-synuclein.

Parkinson's disease (PD) is the second most common neurodegenerative disorder caused due to loss of dopaminergic neurons in substantia nigra pars compacta, which occurs the presence of Lewy bodies made up of Alpha-synuclein (ASN) aggregation resulting in neuronal death. This study aims to identify potent 7,8-Dihydroxyflavone (DHF) derivatives to inhibit the ASN aggregation from in silico analysis. Molecular docking study reveals that carbamic ester derivatives of DHF [DHF-BAHPC (8q), DHF-BAHPEC (8s), DHF-BAHEC (8p), DHF-BDOPC (8c), DHF-BAPEC (8n) and DHF-BAMC (8h)] have good binding affinity towards ASN, when compared with DHF and L-DOPA; their docking score values are -16.3120, -16.1875, -15.2223, -14.3118, -14.2893, -14.2810, -14.0383, and -9.1560 kcal/mol respectively. The in silico pharmacological evaluation shows that these molecules exhibit the drug-likeness and ADMET properties. Molecular dynamics simulation confirms the stability of the molecules with ASN. The intermolecular interaction analyzed under the dynamic condition, allows to identify the candidate which potentially inhibits ASN aggregation. Hence, we propose that DHF derivatives are the potential lead drug molecules and preclinical studies are needed to confirm the promising therapeutic ability against PD.

Binding and stability of indirubin-3-monoxime in the GSK3ß enzyme: a molecular dynamics simulation and binding free energy study.

Alzheimer's disease (AD) is the most devastating neurodegenerative disorder which alters the memory of a person. It is a common form of senile dementia characterized by memory loss, personal skills and disorientation. The current treatment for AD is fully focused to control the disease based on symptoms. Based on the tau hypothesis, GSK3ß is an interesting drug target, this also alters the course of AD. The recent experimental report outlines that the indirubin derivatives inhibit GSK3ß, however, the detailed binding mechanism of indrubin-GSK3ß is not yet known. To understand the exact binding mechanism of indirubin derivatives in the active site of GSK3ß, the molecular conformation, intermolecular interactions, charge density distribution, electrostatic properties and the stability were determined. To accomplish this, indirubin derivatives were screened via molecular docking and further molecular dynamics (MD) and QM/MM-based charge density analysis have been performed. The molecular docking was carried out to investigate the binding affinity and the intermolecular interactions of indirubin molecule in the active site of GSK3ß. QM/MM based charge density (CD) analysis has been carried out to emphasize the nature of chemical bonding (topology of electron density) and the electrostatic properties of ligand in the binding pocket. We have performed the CD analysis of intermolecular interaction between indirubin-3-monoxime and the active site amino acids of GSK3ß. Further, the stability of the molecule has been confirmed from the MD simulation and the binding free energy of the indirubin-3-monoxime-GSK3ß complex has been determined using MM/PBSA method to validate the binding affinity of indirubin-3-monoxime.Communicated by Ramaswamy H. Sarma.

Exploring the different environments effect of piperine via combined crystallographic, QM/MM and molecular dynamics simulation study.

Piperine is a pungent alkaloid, largely present in the skin of pepper. It is the most active component of pepper and being used as a medicine in many Asian countries. The effect of piperine on memory impairment and neurodegeneration in Alzheimer's disease model has been investigated. In the present study, we aim to investigate the effect of piperine molecule in different environments (crystal and active site of proteins) from crystallography, molecular docking, QM/MM based charge density analysis and molecular dynamic simulation. The crystal structure of piperine has been used to determine the topological electron density of intermolecular interactions. The O-atoms of piperine is forming C-H⋅⋅⋅O interactions with the neighboring molecules in the crystal, these interactions also confirmed from the Hirshfeld surface. Further, to understand the nature of interactions and the conformational flexibility of piperine in the active site of recombinant human acetylcholinesterase (rhAChE), molecular docking analysis has been performed. The selected docked complex suggests favorable hydrogen bonding and hydrophobic interactions with rhAChE enzyme; notably, the O3 atom of piperine molecule forms strong hydrogen bonding interaction with Glu202 at 1.8 Å. To determine the charge density distribution and the electrostatic properties of piperine molecule in the active site of rhAChE, the piperine-rhAChE complex was minimized at QM/MM energy level; in which, the binding pocket with piperine was considered as QM region. The charge density analysis of piperine and the interacting amino acid groups have been carried out. The topological analysis of O3⋯H-O/Glu202 hydrogen bonding interaction exhibits strong interactions and the electron density ρcp(r): 0.242 eÅ-3 and the Laplacian ∇2ρcp(r): 3.176 eÅ-5 respectively. These results were compared with the corresponding molecule present in the crystal and gas phase environments of piperine. The comparison of active site structure with the corresponding crystal phase and gas phase structures reveal that piperine exhibits large conformational modification in the active site. The molecular dynamics simulation and binding free energy calculations were performed, this gives the stability, binding affinity of the molecule in the active site of rhAChE. The O3⋯H-O/Glu202 interaction shows the high stability (89.2%), this was confirmed from the stability of hydrogen bond analysis. The binding free energy was used to measure the rate of inhibition of enzyme in the presence of ligand molecule. The comparative study allows to understand the nature of piperine molecule in the gas and crystal phases, and amino acids environment.

Investigation of intermolecular interactions and stability of verubecestat in the active site of BACE1: Development of first model from QM/MM-based charge density and MD analysis.

Alzheimer disease (AD) is a cruel neurodegenerative disorder caused by the deposition of amyloid ß (Aß) peptide inside the brain. The ß-secretase (beta amyloid precursor protein (APP) cleaving enzyme 1, BACE1) is one of the enzymes involved in the cleavage of APP that leads to the Aß formation and it is the primary target for the treatment of AD. Recent report outlines that verubecestat molecule strongly inhibits BACE1; however, its structure, binding mechanism and the stability in the active site of BACE1 are not yet known. The present study aims to determine the structure, binding affinity and the stability of verubecestat molecule in the active site of BACE1 from the molecular docking, quantum mechanics/molecular mechanics (QM/MM)-based charge density analysis and molecular dynamics simulation. Verubecestat molecule was docked at BACE1; it shows high binding affinity towards BACE1. Further, the conformational geometry and the intermolecular interactions of verubecestat in the active site of BACE1 were determined. The molecule forms strong interaction with the neighboring amino acids in the active site of BACE1. The onsite QM/MM-based charge density analysis reveals the nature of charge density distribution and the topological properties of intermolecular interactions of verubecestat molecule in the active site of BACE1. The calculated electrostatic potential (ESP) of verubecestat in the active site of BACE1 displays high negative and positive ESP regions of the molecule. This onsite QM/MM analysis is more relevant to the physiological situation. The molecular dynamics simulation has been performed, which confirms the high stability and compactness of verubecestat in the active site of BACE1. The MM-generalized Born surface area and MM-Poisson Boltzmann surface area free energy calculations of verubecestat-BACE1 also confirm the high binding affinity of verubecestat. Communicated by Ramaswamy H. Sarma.