Unveiling Cathepsin B inhibition with repurposed drugs for anticancer and anti-Alzheimer's drug discovery

Abstract

Alzheimer's disease (AD) is characterized by the aggregation of amyloid β (Aβ) peptides and the formation of plaques in the brain, primarily derived from the proteolytic degradation of amyloid precursor protein (APP). Cathepsin B (CatB) is a cysteine protease that plays a pivotal role in this process, making it a potential target for the development of anti-Alzheimer's therapies. Apart from AD, CatB is implicated in various physiological and pathological processes, including cancer. Given the critical role of CatB in these diseases, identifying effective inhibitors is of significant therapeutic interest. In this study, we employed a systematic virtual screening approach using repurposed molecules from the DrugBank database to identify potential CatB inhibitors. Primarily, we focused on binding affinities and selectivity to pinpoint potential hits against CatB. Two repurposed molecules, Lurasidone and Paliperidone, emerged as promising candidates with significant affinity for CatB. These molecules demonstrated favorable drug profiles and exhibited preferential binding to the catalytic pocket of CatB via interacting with functionally significant residues. To further explore the binding mechanism and stability of the CatB-drug complexes, molecular dynamics (MD) simulations were conducted for 500 ns. The results revealed that CatB and Lurasidone, as well as Paliperidone, form stable complexes throughout the simulation. Taken together, the findings suggest that Lurasidone and Paliperidone can act as repurposed CatB inhibitors with potential applications in the development of therapeutics against AD and other CatB-associated diseases after further validation.

Fig 1. CatB in complex with the screened molecules.

(A) Cartoon view of CatB with Lurasidone (green), Paliperidone (yellow), and Ca-07Me (cyan). (B) Magnified cartoon view of CatB interacting residues with the elucidated molecules. (C) Charged view of CatB binding pocket filled by the elucidated molecules.

Fig 2

The two-dimensional representation of CatB residues and their interaction with (A) Lurasidone, (B) Paliperidone, and (C) Ca-074Me.

Fig 3. Structural dynamics of CatB upon Lurasidone, Paliperidone, and Ca-074Me binding.

(A) RMSD plot of CatB in complex with Lurasidone and Paliperidone. (B) RMSF plot of CatB and its complex with Lurasidone and Paliperidone. The lower panels illustrate the distribution of the values as a probability distribution function (PDF).

Fig 4. Structural compactness of CatB before and after Lurasidone, Paliperidone, and Ca-074Me binding.

(A) The radius of gyration plot and (B) Solvent-accessibility plot of CatB with Lurasidone, Paliperidone, and Ca-074Me binding.

Fig 5. Dynamics of hydrogen bonds.

(A) Hydrogen bonding in CatB, before and after Lurasidone, Paliperidone, and Ca-074Me binding. (B) The probability density function (PDF) of the hydrogen bond numbers.

Fig 6

Intermolecular hydrogen bonds between CatB and (A) Lurasidone, (B) Paliperidone, and (C) Ca-074Me.

Fig 7. Conformational projection in principal component analysis.

(A) 2D projection of CatB, CatB-Lurasidone, CatB-Paliperidone, and CatB-Ca-074Me. (B) Time evolution of the trajectories.

Fig 8

Free energy landscapes (FELs) plots of (A) free CatB, (B) CatB-Lurasidone, (C) CatB-Paliperidone, and (D) free CATB-Ca-074Me. Lower panels showed the most stable conformations of CatB, and its docked complexes fetched from the global minimum.