β-secretase inhibitors for Alzheimer’s disease: identification using pharmacoinformatics
22 Jan 2019-Journal of Biomolecular Structure & Dynamics (Taylor & Francis)-Vol. 37, Iss: 2, pp 503-522
TL;DR: Values of RMSD, RMSF, Rg in molecular dynamics study and binding energies unquestionably explained that final screened molecules formed stable complexes inside the receptor cavity of BACE1 and may be potential therapeutic agents for Alzheimer’s disease.
Abstract: In this study we searched for potential β-site amyloid precursor protein cleaving enzyme1 (BACE1) inhibitors using pharmacoinformatics. A large dataset containing 7155 known BACE1 inhibitors was ev...
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TL;DR: A concerted effort to tackle this dreaded disease as Open Source Drug Discovery for Tuberculosis is named with the power of genomics, computational technologies and participation of young and brilliant talent from Universities and Industrial partners with a strong inclination to address this important scourge.
Abstract: Tuberculosis is a ravaging disease killing one person in every 1.5 minutes in India alone. Someone in the world is newly infected with TB bacilli every second. Overall, one-third of the world's population is currently infected with the TB bacillus. Left untreated, each person with active TB disease will infect on average between 10 and 15 people every year. 450 000 new MDR-TB cases are estimated to occur every year. Estimated 5% of TB patients are HIV infected. Although the complete genome sequence of the causative pathogen _Mycobacterium tuberculosis_ was published about a decade ago and many years of painstaking efforts have been invested, we are still far from having a good, fast acting drug and vaccine which confers long lasting protection. Despite increasing investment, led by charities including the Gates Foundation, no novel drugs for TB have entered the market for many years.Novel mechanisms for attracting funding, particularly private sector funding, into this research area are desperately needed. We wish to bring in the power of genomics, computational technologies and participation of young and brilliant talent from Universities and Industrial partners with a strong inclination to apply a concerted effort to address this important scourge. All researchers contribute data on tuberculosis drug targets and active molecules through a copyleft agreement; anyone who is prepared to keep to this may participate. All the data is Clickwrap protected and credit sharing will be based on a novel and flexible micro-attribution system. This system is aimed at providing due credit through an active process. Various levels of investigators shall have appropriate levels of rights, recognition and responsibilities. Another valuable aspect is the partnerships of Industry with belief in Open Source systems and models. We name this concerted effort to tackle this dreaded disease as Open Source Drug Discovery for Tuberculosis.
63 citations
TL;DR: Treatment with plasma exchange plus therapeutic albumin replacement in patients with Alzheimer's disease induced mobilization of plasma and cerebrospinal fluid amyloid β protein associated with an improvement in memory and language functions, as well as the stabilization of brain perfusion, which persisted after treatment discontinuation.
Abstract: Introduction Preliminary studies have shown that treatment with plasma exchange (PE) plus therapeutic albumin replacement in patients with Alzheimer's disease (AD) induced mobilization of plasma and cerebrospinal fluid amyloid β protein, associated with an improvement in memory and language functions, as well as the stabilization of brain perfusion, which persisted after treatment discontinuation. Methods Alzheimer's Management By Albumin Replacement (AMBAR) is a multicenter, randomized, blinded and placebo-controlled, parallel-group, phase IIb/III trial enrolling patients with mild to moderate AD. The study evaluates PE with different replacement volumes of therapeutic albumin (5% and 20% Albutein®, Grifols), with or without intravenous immunoglobulin (Flebogamma® 5% DIF, Grifols). Patients are randomized to one of three active treatment groups or one control (sham PE) group (1:1:1:1). The intervention regime includes a first 6-week stage of intensive treatment, followed by a second 12-month stage of maintenance treatment. The change from the baseline to the end of treatment periods in the ADAS-Cog and ADCS-ADL scores are the coprimary efficacy variables. Secondary efficacy variables include change from the baseline in scores on cognitive, functional, behavioral, and overall progression tests; changes in plasma and cerebrospinal fluid levels of amyloid β and tau protein; and assessment of structural and functional changes in brain areas of interest. Safety and tolerability are assessed. Results The study has enrolled 496 patients from 41 centers (19 in Spain and 22 in the USA); 347 of these patients were randomized and underwent close to 5000 PEs, of which approximately 25% were sham PEs. Discussion We present an innovative approach for treating AD. The study has been designed to demonstrate clinical efficacy, defined as slow decline of the patient's cognition and brain function. The sample size has adequate power to detect differences between any of the active treatment groups and the control group, as well as between the three active treatment groups combined and the control group.
59 citations
Cites background from "β-secretase inhibitors for Alzheime..."
...Similarly, inhibition or modulation of major players involved in the neurotoxic Ab-generating, such as b-secretase and g-secretase, appear to be key therapeutic targets against AD [7,8]....
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TL;DR: The structure of the compound was found to play a vital role in the inhibitory efficiency, validating previous Structure Activity Relationship (SAR) reviews for coumarin and magnifying the probability of their usage as AD drugs and re-emphasizes the significance of drug delivery media while considering the inhibition potencies of targeted drugs.
Abstract: The inhibitory efficacy of two substituted coumarin derivatives on the activity of neurodegenerative enzyme acetylcholinesterase (AChE) was assessed in aqueous buffer as well as in the presence of ...
28 citations
Additional excerpts
...…experimentally (Azam et al., 2017; Ferreira Neto et al., 2017; Gurung, Aguan, Mitra, & Bhattacharjee, 2017; Hojati, Ghahghaei, & Lagzian, 2017; Islam & Pillay, 2018) and also through pharmacophore screening (Iqbal, Anantha Krishnan, & Gunase- karan, 2017; Jafari et al., 2018; Malik,…...
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TL;DR: This present study virtually screened the MCULE database containing almost 36 million compounds against the structure of a Zaire Ebola viral protein (VP) 35 and a consensus scoring of both MCULE and CLCDDW docking programs remarked five compounds as potential hits, with compound A appearing to be the most promising hit compound.
Abstract: Ebola virus (EBOV) is a lethal human pathogen with a risk of global spread of its zoonotic infections, and Ebolavirus Zaire specifically has the highest fatality rate amongst other species. There i...
23 citations
Cites background from "β-secretase inhibitors for Alzheime..."
...Moreover, virtual screening enables reduction of the computational sampling space and thus makes computational calculations more tractable (Barcellos et al., 2018; Cavuturu, Bhandare, Ramaswamy, & Arumugam, 2018; Islam & Pillay, 2018; Mirza & Ikram, 2016)....
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TL;DR: Four food compounds were proposed as CDK2 inhibitors based on strong binding interaction profiles with the lowest binding interactions affinity and energy values, and may be crucial to stop the hyperproliferation in cancer cells subjected to experimental validation.
Abstract: The cyclin-dependent kinase-2 (CDK2) belongs to the protein kinase family and its overexpression leads to an unusual regulation of cell-cycle which directly linked with hyperproliferation in many cancer cell types. CDK2 activation spontaneously promotes the cell cycle progression and also involved in a large number of cellular processes including cell cycle regulation, DNA replication, DNA damage response and apoptotic pathways, therefore targeting the CDK2 can be reemerged as a therapeutic boulevard to restrain cancer cell proliferation. For the last two decades, emerging evidences suggested that CDK2 inhibition draws out some antitumor/anticancer activity, which has driven the research possibility for developing next-generation newer or cost-effective inhibitors with greater specificity to CDK2. In the current work, compounds from the FooDB - a world’s largest food constituents database was retrieved and curated and followed by multi-pharmacoinformatics approaches adopted to find out potential CDK2 inhibitors. The curated dataset was considered for screening through “Virtual Screening Workflow” (VSW) employed in Schrodinger suite. The numbers of cost-effective food constituents were reduced by removing low potential molecules in terms of interaction affinity and further explored for pharmacokinetics analysis. Based on strong binding interaction profiles with the lowest binding interactions affinity and energy values, four food compounds were proposed as CDK2 inhibitors. A number of key analyzing parameters from molecular dynamics (MD) simulations studies were successfully substantiated that all four proposed food compounds can act as CDK2 inhibitors based on their proficient structural and molecular interactions integrity with CDK2 protein following in the active site cavity. Furthermore, the binding free energy was calculated using the MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) approach from the entire trajectory frames derived in MD simulation revealed strong interaction affinity. The binding free energy was found to be in the range of −991.831 to −210.452 kJ/mol. High binding free energy was undoubtedly explained that all molecules possess strong affection towards CDK2. Hence, proposed molecules may be crucial to stop the hyperproliferation in cancer cells subjected to experimental validation.
23 citations
References
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TL;DR: The CHARMM (Chemistry at Harvard Macromolecular Mechanics) as discussed by the authors is a computer program that uses empirical energy functions to model macromolescular systems, and it can read or model build structures, energy minimize them by first- or second-derivative techniques, perform a normal mode or molecular dynamics simulation, and analyze the structural, equilibrium, and dynamic properties determined in these calculations.
Abstract: CHARMM (Chemistry at HARvard Macromolecular Mechanics) is a highly flexible computer program which uses empirical energy functions to model macromolecular systems. The program can read or model build structures, energy minimize them by first- or second-derivative techniques, perform a normal mode or molecular dynamics simulation, and analyze the structural, equilibrium, and dynamic properties determined in these calculations. The operations that CHARMM can perform are described, and some implementation details are given. A set of parameters for the empirical energy function and a sample run are included.
14,725 citations
"β-secretase inhibitors for Alzheime..." refers methods in this paper
...For each compound, the coordinates were corrected, atoms were typed and energy was minimized using the modified CHARMm force field (Brooks et al., 1983; Momany & Rone, 1992)....
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TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
Abstract: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415) Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described Turbidimetric solubility measurement is described and applied to known drugs High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism Recent work on linear free energy relationships and Log P approaches are critically reviewed Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements
14,026 citations
Johns Hopkins University1, Johns Hopkins University School of Medicine2, Mayo Clinic3, McGill University4, Harvard University5, University of California, Irvine6, University of Pittsburgh7, Columbia University Medical Center8, Eli Lilly and Company9, Washington University in St. Louis10, UCL Institute of Neurology11, VU University Medical Center12, Alzheimer's Association13, Northwestern University14, National Institutes of Health15
TL;DR: The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available.
Abstract: The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.
13,710 citations
TL;DR: GROMACS is one of the most widely used open-source and free software codes in chemistry, used primarily for dynamical simulations of biomolecules, and provides a rich set of calculation types.
Abstract: GROMACS is one of the most widely used open-source and free software codes in chemistry, used primarily for dynamical simulations of biomolecules. It provides a rich set of calculation types, prepa ...
12,985 citations
"β-secretase inhibitors for Alzheime..." refers methods in this paper
...2 (Abraham et al., 2015) used for molecular dynamics simulation....
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...The DS was used for the pharmacophore, virtual screening, molecular docking and binding energy calculation studies whereas Gromacs 5.1.2 (Abraham et al., 2015) used for molecular dynamics simulation....
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TL;DR: Evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics and provided discrete biochemical targets for drug screening and development.
Abstract: Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...
5,890 citations
"β-secretase inhibitors for Alzheime..." refers background in this paper
...…disease (AD) is an incurable age-related neurodegenerative syndrome of the central nervous system which alters the mental capacity (Ghosh & Osswald, 2014) resulting in senile dementia, loss of memory, disorientation, difficulty in speaking or writing, loss of reasoning skills etc. (Selkoe, 2001)....
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