Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent

Charrier, Nicolas; Clarke, Bryan; Demont, Emmanuel H.; Dingwall, Colin; Dunsdon, R.; Hawkins, Julie; 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.2009.03.150

Cited by 46 publications

(30 citation statements)

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“…PLP is simple scoring function which has been shown to correlate fine with protein-ligand binding affinities; Jain evaluated protein-ligand complexes by using an empirical scoring function and PMF is a statistical analysis approach using 3D structure databases to provide a fast and accurate prediction of protein-ligand binding free energies [34]. While LigScore1 uses the partial charges on the atoms of both ligand and receptor to determine whether an atom is polar or nonpolar besides LigScore2 types atoms of ligands and proteins based on rules that employ only formal charges, ignoring partial charges [34].…”

Section: Discussionmentioning

confidence: 99%

“…While LigScore1 uses the partial charges on the atoms of both ligand and receptor to determine whether an atom is polar or nonpolar besides LigScore2 types atoms of ligands and proteins based on rules that employ only formal charges, ignoring partial charges [34].…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Al-Nadaf¹,

Taha²

2015

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“…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%

“…Preliminary the X-ray structures of 14 HEAs bound in the BACE-1 active site, reported by Demont et al [6][7][8][9][10][11] were taken from the Brookhaven Protein Data Bank [27] under the following codes: 2VIE, 2VIY, 2VIZ, 2VJ6, 2VJ7, 2VJ9, 2VNM, 2VNN, 2WEZ, 2WF0, 2WF1, 2WF2, 2WF3 and 2WF4. Residues within a 5 Å radius from the center of 2VNM ligand were included for active site construction.…”

Section: Structure Collectionmentioning

confidence: 99%

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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Peptidomimetic BACE1 Inhibitors for Treatment of Alzheimer's Disease: Design and Evolution

Iserloh¹,

Cumming²

2010

Aspartic Acid Proteases as Therapeutic Targets

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Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent

Cited by 46 publications

References 1 publication

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

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

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

Peptidomimetic BACE1 Inhibitors for Treatment of Alzheimer's Disease: Design and Evolution

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