Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

Structural Modeling of γ-Secretase Aβn Complex Formation and Substrate Processing

(2019) Manuel Hitzenberger et al.   ACS Chemical Neuroscience

Disclosing the template-induced misfolding mechanism of Tau protein by studying the dissociation process of boundary chain from the formed Tau fibril based on the steered molecular dynamics simulation

(2019) Hongli Liu et al.   ACS Chemical Neuroscience

Recognition of the amyloid precursor protein by human γ-secretase

(2019) Rui Zhou et al.   SCIENCE

Structure Based Design and Molecular Docking Studies for Phosphorylated Tau Inhibitors in Alzheimer’s Disease

(2019) Jangampalli Pradeepkiran et al.   Cells

The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention?

(2019) Yann Fichou et al.   Acta Neuropathologica Communications

Structure-Based Peptide Inhibitor Design of Amyloid-β Aggregation

(2019) Jinxia Lu et al.   Frontiers in Molecular Neuroscience

Structure-Based Design of Selective β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2

(2019) Kazuki Fujimoto et al.   JOURNAL OF MEDICINAL CHEMISTRY

Uncovering the Binding Mode of γ -Secretase Inhibitors

(2019) Manuel Hitzenberger et al.   ACS Chemical Neuroscience

Structure and Function of the γ-Secretase Complex

(2019) Michael S. Wolfe   BIOCHEMISTRY

Abnormal platelet amyloid‐β precursor protein metabolism in SAMP8 mice: Evidence for peripheral marker in Alzheimer's disease

(2019) Lizhi Chen et al.   JOURNAL OF CELLULAR PHYSIOLOGY

QSAR Classification Models for Predicting the Activity of Inhibitors of Beta-Secretase (BACE1) Associated with Alzheimer’s Disease

(2019) Ignacio Ponzoni et al.   Scientific Reports

Computational Study on Structure and Aggregation Pathway of Aβ42 Amyloid Protofibril

(2019) MinJun Lee et al.   JOURNAL OF PHYSICAL CHEMISTRY B

Molecular Mechanism of Binding Selectivity of Inhibitors toward BACE1 and BACE2 Revealed by Multiple Short Molecular Dynamics Simulations and Free-Energy Predictions

(2019) Jianzhong Chen et al.   ACS Chemical Neuroscience

Disclosing the Mechanism of Spontaneous Aggregation and Template-Induced Misfolding of the Key Hexapeptide (PHF6) of Tau Protein Based on Molecular Dynamics Simulation

(2019) Hongli Liu et al.   ACS Chemical Neuroscience

Proposal of therapeutic curcumin derivatives for Alzheimer’s disease based on ab initio molecular simulations

(2019) Tomoki Shinzato et al.   CHEMICAL PHYSICS LETTERS

A resurrection of aducanumab for Alzheimer's disease

(2019) Lon Schneider   LANCET NEUROLOGY

Structural Basis of Small Molecule Targetability of Monomeric Tau Protein

(2018) Róbert Kiss et al.   ACS Chemical Neuroscience

Different Positron Emission Tomography Tau Tracers Bind to Multiple Binding Sites on the Tau Fibril: Insight from Computational Modeling

(2018) N. Arul Murugan et al.   ACS Chemical Neuroscience

Simulating the γ-secretase enzyme: Recent advances and future directions

(2018) Rodrigo Aguayo-Ortiz et al.   BIOCHIMIE

A molecular approach in drug development for Alzheimer’s disease

(2018) Snezana Agatonovic-Kustrin et al.   BIOMEDICINE & PHARMACOTHERAPY

Current Therapy and Computational Drug Designing Approaches for Neurodegenerative diseases -with focus on Alzheimer’s and Parkinson’s

(2018) Indrani Bera   Current Signal Transduction Therapy

An Overview on the Clinical Development of Tau-Based Therapeutics

(2018) Miguel Medina   INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

Rational Design of Novel 1,3-Oxazine Based β-Secretase (BACE1) Inhibitors: Incorporation of a Double Bond To Reduce P-gp Efflux Leading to Robust Aβ Reduction in the Brain

(2018) Kouki Fuchino et al.   JOURNAL OF MEDICINAL CHEMISTRY

Tau-targeting therapies for Alzheimer disease

(2018) Erin E. Congdon et al.   Nature Reviews Neurology

Tau Kinetics in Neurons and the Human Central Nervous System

(2018) Chihiro Sato et al.   NEURON

Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease

(2018) Fuyuki Kametani et al.   Frontiers in Neuroscience

The Rational Discovery of a Tau Aggregation Inhibitor

(2018) David W. Baggett et al.   BIOCHEMISTRY

Effective suppression of the modified PHF6 peptide/1N4R Tau amyloid aggregation by intact curcumin, not its degradation products: Another evidence for the pigment as preventive/therapeutic “functional food”

(2018) Nooshin Bijari et al.   INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

d-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors

(2018) Banafsheh Mehrazma et al.   MOLECULES

Structure-Based Drug Designing Recommends HDAC6 Inhibitors To Attenuate Microtubule-Associated Tau-Pathogenesis

(2018) Amir Zeb et al.   ACS Chemical Neuroscience

Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold

(2018) Benjamin Falcon et al.   ACTA NEUROPATHOLOGICA

Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

(2018) Emma Nichols et al.   LANCET NEUROLOGY

Structural basis of Notch recognition by human γ-secretase

(2018) Guanghui Yang et al.   NATURE

Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability

(2018) Alejandra D. Alonso et al.   Frontiers in Cellular Neuroscience

Discovery of imidazopyridines containing isoindoline-1,3-dione framework as a new class of BACE1 inhibitors: Design, synthesis and SAR analysis

(2017) Sara Azimi et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

2-Substituted-thio- N -(4-substituted-thiazol/1 H -imidazol-2-yl)acetamides as BACE1 inhibitors: Synthesis, biological evaluation and docking studies

(2017) Gang Yan et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Multifunctional iminochromene-2H-carboxamide derivatives containing different aminomethylene triazole with BACE1 inhibitory, neuroprotective and metal chelating properties targeting Alzheimer's disease

(2017) Aida Iraji et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010-2015

(2017) Dev Mehta et al.   EXPERT OPINION ON INVESTIGATIONAL DRUGS

Design, Syntheses, and in Vitro Evaluation of New Fluorine-18 Radiolabeled Tau-Labeling Molecular Probes

(2017) Luka Rejc et al.   JOURNAL OF MEDICINAL CHEMISTRY

In Silico Prediction of Ligand Binding Energies in Multiple Therapeutic Targets and Diverse Ligand Sets—A Case Study on BACE1, TYK2, HSP90, and PERK Proteins

(2017) Elizabeth Hatcher Frush et al.   JOURNAL OF PHYSICAL CHEMISTRY B

Why do so many clinical trials of therapies for Alzheimer's disease fail?

(2017) Roy M Anderson et al.   LANCET

Solanezumab: too late in mild Alzheimer's disease?

(2017) The Lancet Neurology   LANCET NEUROLOGY

Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer’s Disease Therapeutic Agents

(2017) Laura Llorach-Pares et al.   Marine Drugs

Cryo-EM structures of tau filaments from Alzheimer’s disease

(2017) Anthony W. P. Fitzpatrick et al.   NATURE

Structure-based inhibitors of tau aggregation

(2017) P. M. Seidler et al.   Nature Chemistry

Atomic-resolution structures from fragmented protein crystals with the cryoEM method MicroED

(2017) M Jason de la Cruz et al.   NATURE METHODS

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

(2017) Jun Wang et al.   Nature Reviews Neurology

Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau

(2017) Yunior Cabrales Fontela et al.   Nature Communications

Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport

(2017) Nadine Ruderisch et al.   EBioMedicine

Truncation of Tau Protein and its Pathological Significance in Alzheimer's Disease

(2017) Francisco García-Sierra et al.   JOURNAL OF ALZHEIMERS DISEASE

C-Glycosylflavones Alleviate Tau Phosphorylation and Amyloid Neurotoxicity through GSK3β Inhibition

(2016) Zhibin Liang et al.   ACS Chemical Neuroscience

Why has therapy development for dementia failed in the last two decades?

(2016) Serge Gauthier et al.   Alzheimers & Dementia

Design and synthesis of curcumin derivatives as tau and amyloid β dual aggregation inhibitors

(2016) Michiaki Okuda et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Microglia in Alzheimer's Disease: The Good, the Bad and the Ugly

(2016) Dario Tejera et al.   Current Alzheimer Research

Asp32 and Asp228 determine the selective inhibition of BACE1 as shown by docking and molecular dynamics simulations

(2016) Maricarmen Hernández-Rodríguez et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Multi-target screening mines hesperidin as a multi-potent inhibitor: Implication in Alzheimer's disease therapeutics

(2016) Sandipan Chakraborty et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

New small-size peptides modulators of the exosite of BACE1 obtained from a structure-based design

(2016) Lucas J. Gutierrez et al.   JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS

Application of Free Energy Perturbation for the Design of BACE1 Inhibitors

(2016) Myriam Ciordia et al.   Journal of Chemical Information and Modeling

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

(2016) Yong-Jin Wu et al.   ACS Medicinal Chemistry Letters

Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials

(2016) Rik Vandenberghe et al.   Alzheimers Research & Therapy

High Resolution Dissection of Reactive Glial Nets in Alzheimer’s Disease

(2016) David S. Bouvier et al.   Scientific Reports

Folding of the Tau Protein on Microtubules

(2015) Harindranath Kadavath et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Treatment Options in Alzheimer´s Disease: The GABA Story

(2015) Maite Solas et al.   CURRENT PHARMACEUTICAL DESIGN

Molecular docking based virtual screening of natural compounds as potential BACE1 inhibitors: 3D QSAR pharmacophore mapping and molecular dynamics analysis

(2015) Akhil Kumar et al.   JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS

An atomic structure of human γ-secretase

(2015) Xiao-chen Bai et al.   NATURE

What does it take to produce a breakthrough drug?

(2015) Dirk Calcoen et al.   NATURE REVIEWS DRUG DISCOVERY

An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities

(2015) Yuan Cheng et al.   ACS Medicinal Chemistry Letters

Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans

(2015) I-Fang Ling et al.   Alzheimers Research & Therapy

Sampling the conformational space of the catalytic subunit of human γ-secretase

(2015) Xiao-chen Bai et al.   eLife

First Selective Dual Inhibitors of Tau Phosphorylation and Beta-Amyloid Aggregation, Two Major Pathogenic Mechanisms in Alzheimer’s Disease

(2014) Marica Mariano et al.   ACS Chemical Neuroscience

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

(2014) Arun K. Ghosh et al.   CHEMICAL SOCIETY REVIEWS

In Silico Screening of Drugs to Find Potential Gamma-Secretase Inhibitors Using Pharmacophore Modeling, QSAR and Molecular Docking Studies

(2014) Arun Raman et al.   COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING

Multi-Target Directed Drugs: A Modern Approach for Design of New Drugs for the treatment of Alzheimer’s Disease

(2014) Kris Simone Tranches Dias et al.   Current Neuropharmacology

The Emerging Link betweenO-GlcNAc and Alzheimer Disease

(2014) Yanping Zhu et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Structural Insight into Tau Protein’s Paradox of Intrinsically Disordered Behavior, Self-Acetylation Activity, and Aggregation

(2014) Yin Luo et al.   Journal of Physical Chemistry Letters

Encompassing receptor flexibility in virtual screening using ensemble docking-based hybrid QSAR: discovery of novel phytochemicals for BACE1 inhibition

(2014) Sandipan Chakraborty et al.   Molecular BioSystems

Computer-aided discovery of novel non-peptide inhibitors against amyloid-beta (Aβ) peptide aggregation for treating Alzheimer's disease

(2014) Zheng-Li Zhou et al.   MOLECULAR SIMULATION

Long-term effects of amyloid, hypometabolism, and atrophy on neuropsychological functions

(2014) R. Ossenkoppele et al.   NEUROLOGY

The γ-secretase complex: from structure to function

(2014) Xian Zhang et al.   Frontiers in Cellular Neuroscience

Tau-Derived-Hexapeptide 306VQIVYK311 Aggregation Inhibitors: Nitrocatechol Moiety as A Pharmacophore In Drug Design

(2013) Tarek Mohamed et al.   ACS Chemical Neuroscience

Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation

(2013) Lea Tenenholz Grinberg et al.   ACTA NEUROPATHOLOGICA

The Alzheimer’s β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques

(2013) Patty C. Kandalepas et al.   ACTA NEUROPATHOLOGICA

Molecular Hairpin: A Possible Model for Inhibition of Tau Aggregation by Tannic Acid

(2013) Junliang Yao et al.   BIOCHEMISTRY

γ-Secretase inhibitors and modulators

(2013) Todd E. Golde et al.   BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES

Allosteric inhibition of BACE1 by an exosite-binding antibody

(2013) Weiru Wang et al.   CURRENT OPINION IN STRUCTURAL BIOLOGY

The role of protein glycosylation in Alzheimer disease

(2013) Sophia Schedin-Weiss et al.   FEBS Journal

Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance

(2013) Casey Cook et al.   HUMAN MOLECULAR GENETICS

Structural and functional insights into the anti-BACE1 Fab fragment that recognizes the BACE1 exosite

(2013) Lucas Joel Gutiérrez et al.   JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS

Identification of small-molecule binding pockets in the soluble monomeric form of the Aβ42 peptide

(2013) Maximillian Zhu et al.   JOURNAL OF CHEMICAL PHYSICS

Discovery of Biphenylacetamide-Derived Inhibitors of BACE1 Using de Novo Structure-Based Molecular Design

(2013) N. Yi Mok et al.   JOURNAL OF MEDICINAL CHEMISTRY

A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease

(2013) Rachelle S. Doody et al.   NEW ENGLAND JOURNAL OF MEDICINE

Computational Design of New Peptide Inhibitors for Amyloid Beta (Aβ) Aggregation in Alzheimer's Disease: Application of a Novel Methodology

(2013) Gözde Eskici et al.   PLoS One

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

(2013) E.-M. Mandelkow et al.   Cold Spring Harbor Perspectives in Medicine

Simple Structure-Based Approach for Predicting the Activity of Inhibitors of Beta-Secretase (BACE1) Associated with Alzheimer’s Disease

(2012) Anthony F. Nastase et al.   Journal of Chemical Information and Modeling

Design of β-Amyloid Aggregation Inhibitors from a Predicted Structural Motif

(2012) Paul A. Novick et al.   JOURNAL OF MEDICINAL CHEMISTRY

Design and Validation of Bicyclic Iminopyrimidinones As Beta Amyloid Cleaving Enzyme-1 (BACE1) Inhibitors: Conformational Constraint to Favor a Bioactive Conformation

(2012) Mihirbaran Mandal et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides

(2012) Heinrich Rueeger et al.   JOURNAL OF MEDICINAL CHEMISTRY

Conformational Restriction Approach to β-Secretase (BACE1) Inhibitors: Effect of a Cyclopropane Ring To Induce an Alternative Binding Mode

(2012) Shuji Yonezawa et al.   JOURNAL OF MEDICINAL CHEMISTRY

The Backbone Dynamics of the Amyloid Precursor Protein Transmembrane Helix Provides a Rationale for the Sequential Cleavage Mechanism of γ-Secretase

(2012) Oxana Pester et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction

(2012) Andrew W. Stamford et al.   ACS Medicinal Chemistry Letters

The Membrane-Bound Aspartyl Protease BACE1: Molecular and Functional Properties in Alzheimer’s Disease and Beyond

(2012) Bastian Dislich et al.   Frontiers in Physiology

Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations

(2011) Yechun Xu et al.   ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY

Tau pathology in children and young adults: can you still be unconditionally baptist?

(2011) Charles Duyckaerts   ACTA NEUROPATHOLOGICA

Review of Synthesis, Biological Assay and QSAR Studies of β-Secretase Inhibitors

(2011) Helena Nino et al.   Current Computer-Aided Drug Design

From Fragment Screening to In Vivo Efficacy: Optimization of a Series of 2-Aminoquinolines as Potent Inhibitors of Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)

(2011) Yuan Cheng et al.   JOURNAL OF MEDICINAL CHEMISTRY

Phosphorylation of microtubule-associated protein tau by AMPK-related kinases

(2011) Hirotaka Yoshida et al.   JOURNAL OF NEUROCHEMISTRY

A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-  Production in Vivo

(2011) J. K. Atwal et al.   Science Translational Medicine

BACE1 Inhibitor Peptides: Can an Infinitely Small kcat Value Turn the Substrate of an Enzyme into Its Inhibitor?

(2011) Yoshio Hamada et al.   ACS Medicinal Chemistry Letters

The acetylation of tau inhibits its function and promotes pathological tau aggregation

(2011) Todd J. Cohen et al.   Nature Communications

Self-organizing molecular field analysis on human β-secretase nonpeptide inhibitors: 5, 5-disubstituted aminohydantoins

(2010) Zhi Li et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Ligand - based virtual screening procedure for the prediction and the identification of novel β-amyloid aggregation inhibitors using Kohonen maps and Counterpropagation Artificial Neural Networks

(2010) Antreas Afantitis et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Structural and Thermodynamic Characteristics of the Exosite Binding Pocket on the Human BACE1: A Molecular Modeling Approach

(2010) Lucas J. Gutierrez et al.   JOURNAL OF PHYSICAL CHEMISTRY A

Emerging principles in protease-based drug discovery

(2010) Marcin Drag et al.   NATURE REVIEWS DRUG DISCOVERY

Synaptic and Endosomal Localization of Active γ-Secretase in Rat Brain

(2010) Susanne Frykman et al.   PLoS One

Effects of donepezil on amyloid-β and synapse density in the Tg2576 mouse model of Alzheimer's disease

(2009) Hongxin Dong et al.   BRAIN RESEARCH

Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options

(2009) Bayani Uttara et al.   Current Neuropharmacology

Targeting Aβ and tau in Alzheimer's disease, an early interim report

(2009) Todd E. Golde et al.   EXPERIMENTAL NEUROLOGY

Hybrid Structure-Based Virtual Screening Protocol for the Identification of Novel BACE1 Inhibitors

(2009) R. S. K Vijayan et al.   Journal of Chemical Information and Modeling

Design and Synthesis of 5,5′-Disubstituted Aminohydantoins as Potent and Selective Human β-Secretase (BACE1) Inhibitors

(2009) Michael S. Malamas et al.   JOURNAL OF MEDICINAL CHEMISTRY

Two-Dimensional Electrophoresis of Tau Mutants Reveals Specific Phosphorylation Pattern Likely Linked to Early Tau Conformational Changes

(2009) Alexis Bretteville et al.   PLoS One

Inhibition and modulation of γ-secretase for Alzheimer’s disease

(2008) Michael S. Wolfe   Neurotherapeutics