Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics

Charrier, Nicolas; Clarke, Bryan; Cutler, Leanne; Demont, Emmanuel H.; Dingwall, Colin; Dunsdon, R.; Hawkins, Julie; Howes, Colin; Hubbard, Julia A.; Hussain, Ishrut; Maile, G.; Matico, Rosalie; Mosley, J.; Naylor, Alan; O’Brien, Alistair; Redshaw, Sally; Rowland, Paul; Soleil, V.; Smith, Kathrine J.; Sweitzer, Sharon; Theobald, Pam; Vesey, D.; Walter, Daryl S.; Wayne, Gareth

doi:10.1016/j.bmcl.2009.03.165

Cited by 47 publications

(25 citation statements)

References 12 publications

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“…Despite significant progress in understanding the molecular and cellular effects of HEAs has been done [9,[12][13][14], a few theoretical studies, to the best of our knowledge, have been reported [15][16][17][18]. More particularly, such an approach is expected to shed some light onto the role of protein-ligand interactions for this system.…”

Section: Introductionmentioning

confidence: 89%

“…Recently, it was described the first and second generation of novel hydroxyethylamines (HEAs) acting as BACE-1 inhibitors with; nanomolar potency in cells, favorable pharmacokinetic properties and orally bioavailables [6][7][8][9][10][11]. Despite significant progress in understanding the molecular and cellular effects of HEAs has been done [9,[12][13][14], a few theoretical studies, to the best of our knowledge, have been reported [15][16][17][18].…”

Section: Introductionmentioning

confidence: 94%

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Quantum mechanics study of the hydroxyethylamines–BACE-1 active site interaction energies

Gueto-Tettay

Drosos

Vivas‐Reyes

2011

J Comput Aided Mol Des

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The identification of BACE-1, a key enzyme in the production of Amyloid-β (Aβ) peptides, generated by the proteolytic processing of amyloid precursor protein, was a major advance in the field of Alzheimer's disease as this pathology is characterized by the presence of extracellular senile plaques, mainly comprised of Aβ peptides. Hydroxyethylamines have demonstrated a remarkable potential, like candidate drugs, for this disease using BACE-1 as target. Density Functional Theory calculations were employed to estimate interaction energies for the complexes formed between the hydroxyethylamine derivated inhibitors and 24 residues in the BACE-1 active site. The collected data offered not only a general but a particular quantitative description that gives a deep insight of the interactions in the active site, showing at the same time how ligand structural variations affect them. Polar interactions are the major energetic contributors for complex stabilization and those ones with charged aspartate residues are highlighted, as they contribute over 90% of the total attractive interaction energy. Ligand-ARG296 residue interaction reports the most repulsive value and decreasing of the magnitude of this repulsion can be a key feature for the design of novel and more potent BACE-1 inhibitors. Also it was explained why sultam derivated BACE-1 inhibitors are better ones than lactam based. Hydrophobic interactions concentrated at S1 zone and other relevant repulsions and attractions were also evaluated. The comparison of two different theory levels (X3LYP and M062X) allowed to confirm the relevance of the detected interactions as each theory level has its own strength to depict the forces involved, as is the case of M062X which is better describing the hydrophobic interactions. Those facts were also evaluated and confirmed by comparing the quantitative trend, of selected ligand-residue interactions, with MP2 theory level as reference standard method for electrostatic plus dispersion energies.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 94%

Quantum mechanics study of the hydroxyethylamines–BACE-1 active site interaction energies

Gueto-Tettay

Drosos

Vivas‐Reyes

2011

J Comput Aided Mol Des

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“…Hydrogen atoms were added to the protein utilizing DS 2.0 templates for protein residues. Gasteiger-Marsili charges were assigned to the protein atoms as implemented within DS 2.5 [33,34]. The protein structures were utilized in subsequent docking experiments without energy minimization.…”

Section: S12 Preparation Of Crystal Structuresmentioning

confidence: 99%

Identification of Small Molecule Memapsin Inhibitors via Computation-based Virtual Screening

Al-Nadaf¹,

Taha²

2015

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Background: Alzheimer's disease (AD) is a degenerative disease of the brain common form of dementia. A variety of therapeutic strategies for modulating the progression or prevention of AD are currently being investigated. The etiology of the disease is characterized by aggregates of amyloid plaques, largely composed of amyloid-β peptide formed from the amyloid precursor protein cleaved by Memapsin 2(Beta-secretase / BACE1). Based on its key role in the β -amyloid cascade, inhibition of Memapsin 2 is widely recognized as one of the most promising therapeutic approaches for the treatment and prevention of AD. However, the development of small molecule, brain penetrant Memapsin 2 inhibitors has been challenging. Method: Molecular docking study using LigandFit Docking and Scoring as well as LibDock Docking functions were performed as a preliminary in-silico screening test for National Cancer Institute (NCI) database using binding pocket of Memapsin. Followed by in-vitro enzyme inhibition assay, High-ranking docked conformers and poses were scored using seven scoring functions. The validation for our docking-scoring procedure was performed through employing the same conditions to dock a well-known Memapsin inhibitor IO2. High ranking compounds were evaluated in vitro using Memapsin fluorescence resonance energy transfer (FRET) assay. Results: The docking simulation resulted in a close model to the crystallographic structure. Five of the important interactions are shared between the co-crystallized ligand and in-silico hits. Virtual screening identified low micromolar inhibitory leads from the NCI list of compounds. The most potent hit exhibited Memapsin IC 50 values of 11.1 µM in enzymatic assay. Conclusion: We have identified a low micro-molar Memapsin inhibitor with IC 50 of 11.1 µM. Our results suggest that in silico high-throughput screening approach can serve as useful source to identify new hits which can be used as lead candidate for synthetic modification in order to reach more potent enzyme inhibitors.

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“…These plaques consist of aggregated amyloid--peptide (A ) deposits, -protein aggregation, oxidative stress, dyshomeostasis of biometals, and low acetylcholine (ACh) levels and plays significant role in the pathophysiology of the disease [7]. Nowadays, the most used therapeutic treatment against AD involves the use of acetylcholinesterase inhibitors (AChEIs) that improve AD symptoms by AChE inhibition [8][9][10][11][12]. The reversible AChE inhibition has become the promising target for the treatment of AD which is mainly associated with low in vivo AChE levels.…”

Section: Introductionmentioning

confidence: 99%

Scale Alpha and Beta of Quantitative Convergence and Chemical Reactivity Analysis in Dual Cholinesterase/Monoamine Oxidase Inhibitors for the Alzheimer Disease Treatment Using Density Functional Theory (DFT)

Morales-Bayuelo

Baldiris

Vivas‐Reyes

2013

Journal of Theoretical Chemistry

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Molecular quantum similarity descriptors and Density Functional Theory (DFT) based reactivity descriptors were studied for a series of cholinesterase/monoamine oxidase inhibitors used for the Alzheimer's disease treatment (AD). This theoretical study is expected to shed some light onto some molecular aspects that could contribute to the knowledge of the molecular mechanics behind interactions of these molecules with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamine oxidase (MAO) A and B. The Topogeometrical Superposition Algorithm to handle flexible molecules (TGSA-Flex) alignment method was used to solve the problem of the relative orientation in the quantum similarity (QS) field. Using the molecular quantum similarity (MQS) field and reactivity descriptors supported in the DFT was possible the quantification of the steric and electrostatic effects through of the Coulomb and Overlap quantitative convergence scales (alpha and beta). In addition, an analysis of reactivity indexes is development, using global and local descriptors, identifying the binding sites and selectivity in the (cholinesterase/monoamine oxidase) inhibitors, understanding the retrodonor process, and showing new insight for drugs design in a disease of difficult control as Alzheimer.

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Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics

Cited by 47 publications

References 12 publications

Quantum mechanics study of the hydroxyethylamines–BACE-1 active site interaction energies

Quantum mechanics study of the hydroxyethylamines–BACE-1 active site interaction energies

Identification of Small Molecule Memapsin Inhibitors via Computation-based Virtual Screening

Scale Alpha and Beta of Quantitative Convergence and Chemical Reactivity Analysis in Dual Cholinesterase/Monoamine Oxidase Inhibitors for the Alzheimer Disease Treatment Using Density Functional Theory (DFT)

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