Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: Structure–activity relationship of P2′ substituents

Truong, Anh P.; Probst, Gary D.; Aquino, Jose; Fang, Lanlan; Brogley, Louis; Sealy, Jennifer M.; Hom, Roy K.; Tucker, John; John, Varghese; Tung, Jay S.; Pleiss, Michael A.; Konradi, Andrei W.; Sham, Hing L.; Dappen, Michael S.; Toth, G.; Yao, Nanhua; Brecht, E.; Pan, Hongyu; Artis, Dean R.; Ruslim, Lany; Bova, Michael P.; Sinha, Sukanto; Yednock, Ted; Zmolek, Wes; Quinn, Kevin P.; Sauer, John‐Michael

doi:10.1016/j.bmcl.2010.06.112

Cited by 23 publications

(10 citation statements)

References 61 publications

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“…A set of 92 compounds was collected from ChEMBL, − with the aim of finding three series of related analogues for which MDCK permeability data were available. Molecules in this data set were not synthesized at Genentech.…”

Section: Methodsmentioning

confidence: 99%

Predicting Passive Permeability of Drug-like Molecules from Chemical Structure: Where Are We?

Broccatelli¹,

Salphati²,

Plise³

et al. 2016

Mol. Pharmaceutics

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Intestinal absorption in human is routinely predicted in drug discovery using in vitro assays such as permeability in the Madin-Darby canine kidney cell line. In silico models trained on these data are used in drug discovery efforts to prioritize novel chemical targets for synthesis; however, their proprietary nature and the limited validation available, which is usually restricted to predicting in vitro permeability, are barriers to widespread adoption. Because of the categorical nature of the in vitro permeability assay, intrinsic assay variability, and the challenges often encountered when translating in vitro data to an in vivo drug property, validation based solely on in vitro data might not be a good characterization of the usefulness of the in silico tool. In this work, we analyze the performance of three different in silico models in predicting the in vitro and in vivo permeability of 300 marketed drugs and 86 discovery compounds. The models differ in their approach (mechanistic vs quantitative structure-activity relationship) and the degree of complexity; one of them is a linear equation based on seven simple physicochemical descriptors and is presented for the first time in this work. Results show that in silico models can be successfully used to complement the discovery toolbox for characterizing in vivo intestinal permeability, defined using fraction of dose absorbed in human (Fa) and human jejunal permeability (P). While the in vitro permeability models outperformed the in silico approach at predicting each of the in vivo end points explored, the gap in predictivity between the in vitro and the in vivo data was generally comparable to the gap between in silico and in vitro data. The in vitro and in silico approaches shared many of the same outliers, which can often be explained by the route of drug absorption (paracellular vs transcellular, active vs passive). Data suggest that the discovery process can greatly benefit from an early adoption of in silico models for predicting permeability as well as from a careful analysis of the in silico to in vivo disconnects.

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Section: Methodsmentioning

confidence: 99%

Predicting Passive Permeability of Drug-like Molecules from Chemical Structure: Where Are We?

Broccatelli¹,

Salphati²,

Plise³

et al. 2016

Mol. Pharmaceutics

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“…This addition includes the Chk1, Bace, and FXa series first used in ref . Additional ligand series were sourced for FXa from refs − , Bace from ref , and another series focused on changes to an amidinium core, coordinating the catalytic aspartates of Bace in ref , excluding compounds with uncertain protonation state or multiple possible tautomeric states. A representative ligand for each target is shown in Figure .…”

Section: Application To Protein–ligand Bindingmentioning

confidence: 99%

OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules

Roos

Damm

et al. 2019

J. Chem. Theory Comput.

964

909

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Building upon the OPLS3 force field we report on an enhanced model, OPLS3e, that further extends its coverage of medicinally relevant chemical space by addressing limitations in chemotype transferability. OPLS3e accomplishes this by incorporating new parameter types that recognize moieties with greater chemical specificity and integrating an on-the-fly parametrization approach to the assignment of partial charges. As a consequence, OPLS3e leads to greater accuracy against performance benchmarks that assess small molecule conformational propensities, solvation, and protein–ligand binding.

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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: 90%

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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Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: Structure–activity relationship of P2′ substituents

Cited by 23 publications

References 61 publications

Predicting Passive Permeability of Drug-like Molecules from Chemical Structure: Where Are We?

Predicting Passive Permeability of Drug-like Molecules from Chemical Structure: Where Are We?

OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules

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

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