β-amyloid precursor protein cleaving enzyme1 (BACE1) has prominently been an important drug design target implicated in Alzheimer's disease pathway. The failure rate of most of the already tested drugs at different clinical phases remains a major concern. Recently, AM-6494 was reported as a novel potent, highly selective, and orally effective inhibitor against BACE1. AM-6494 displayed no alteration of skin/fur colour in animal studies, an adverse effect common to previous BACE1 inhibitors. However, the atomistic molecular mechanism of BACE1 inhibition by AM-6494 remains unclear. To elucidate the binding mechanism of AM-6494 relative to umibecestat (CNP-520) as well as the structural changes when bound to BACE1, advanced computational techniques such as accelerated MD simulation and principal component analysis have been utilised. The results demonstrated higher binding affinity of AM-6494 at BACE1 with van der Waals as dominant energy contributor compared to umibecestat. Conformational monitoring of the β-hairpin flap covering the active site revealed an effective flap closure when bound with AM-6494 compared to CNP-520, which predominantly alternates between semi-open and closed conformations. The observed effective flap closure of AM-6494 explains its higher inhibitory power towards BACE1. Besides the catalytic Asp32/228 dyad, Tyr14, Leu30, Tyr71 and Gly230 represent critical residues in the potency of these inhibitors at BACE1 binding interface. The findings highlighted in this research provide a basis to explain AM-6494 high inhibitory potency and might assist in the design of new inhibitors with improved selectivity and potency for BACE1.

01 Mar 2021·Biophysical ChemistryQ4 · BIOLOGY

Computational modelling of potent β-secretase (BACE1) inhibitors towards Alzheimer's disease treatment

Q4 · BIOLOGY

Article

Author: Ugbaja, Samuel C ; Sanusi, Zainab K ; Lawal, Monsurat M ; Appiah-Kubi, Patrick ; Kumalo, Hezekiel M

Researchers have identified the β-amyloid precursor protein cleaving enzyme 1 (BACE1) in the multifactorial pathway of Alzheimer's disease (AD) as a drug target. The design and development of molecules to inhibit BACE1 as a potential cure for AD thus remained significant. Herein, we simulated two potent BACE1 inhibitors (AM-6494 and CNP-520) to understand their binding affinity at the atomistic level. AM-6494 is a newly reported potent BACE1 inhibitor with an IC₅₀ value of 0.4 nM in vivo and now picked for preclinical considerations. Umibecestat (CNP-520), which was discontinued at human trials lately, was considered to enable a reasonable evaluation of our results. Using density functional theory (DFT) and Our Own N-layered Integrated molecular Orbital and Molecular Mechanics (ONIOM), we achieved the aim of this investigation. These computational approaches enabled the prediction of the electronic properties of AM-6494 and CNP-520 plus their binding energies when complexed with BACE1. For AM-6494 and CNP-520 interaction with protonated BACE1, the ONIOM calculation gave binding free energy of -62.849 and -33.463 kcal/mol, respectively. In the unprotonated model, we observed binding free energy of -59.758 kcal/mol in AM-6494. Taken together thermochemistry of the process and molecular interaction plot, AM-6494 is more favourable than CNP-520 towards the inhibition of BACE1. The protonated model gave slightly better binding energy than the unprotonated form. However, both models could sufficiently describe ligand binding to BACE1 at the atomistic level. Understanding the detailed molecular interaction of these inhibitors could serve as a basis for pharmacophore exploration towards improved inhibitor design.

01 Jul 2020·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

The development of a structurally distinct series of BACE1 inhibitors via the (Z)-fluoro-olefin amide bioisosteric replacement

Q4 · MEDICINE

Article

Author: Wood, Stephen ; Frohn, Michael ; Qian, Wenyuan ; Bartberger, Michael D ; Liu, Longbin ; Allen, Jennifer R ; Whittington, Douglas A ; Siegmund, Aaron C ; Amegadzie, Albert ; Hickman, Dean ; Bourbeau, Matthew P ; Chen, Ning ; Wen, Paul H ; Tan, Helming

The (Z)-fluoro-olefin amide bioisosteric replacement is an effective tool for addressing various shortcomings of the parent amide. In an effort to fine tune ADME properties of BACE1 preclinical candidate AM-6494, a series of structurally distinct (Z)-fluoro-olefin containing analogs was developed that culminated in compound 15. Herein, we detail design considerations, synthetic challenges, structure activity relationship (SAR) studies, and in vivo properties of an advanced compound in this novel series of BACE1 inhibitors.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Discovery	US	Amgen, Inc.	-

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