A neurotoxic peptide β-amyloid (Aβ) is linked to the beginning of Alzheimer’s disease (AD). The accumulation of amyloid-beta inside mitochondria boosts production of free radical and activation of the apoptotic pathway. Human Presequence Protease (hPreP, PITRM1) is a mitochondrial ATP-independent metalloprotease. It degrades toxic peptides, including mitochondrial presequences and β-amyloid. This enzyme is an attractive target for Alzheimer’s disease drug design because enhancement of it's activity increases the level of Aβ proteolysis.

OTAVAchemicals offers a Human Presequence Protease Agonist Library (1050 compounds in total). It has been carefully designed with two approaches as a special screening library containing compounds with predicted hPreP activating activity. One part of compounds was selected by pharmacophore screening of our Drug-like Green Collection against five-point pharmacophore model offered by Vangavaragu at all. Another part was selected with Bayesian models based on fingerprints and molecular descriptors using as a template agonists of PITRM1 developed by the same authors. Top-scored ligands were picked from both screening, 30% among them overlapped. Physicochemical properties of compounds in the library are related to BBB penetration.

This library comprises molecules with increased potential for CNS bioavailability and provides an excellent basis for Alzheimer’s disease drug discovery projects.

References:

• Jhansi Rani Vangavaragu, Koteswara Rao Valasani, Xueqi Gan, Shirley ShiDu Yan. Identification of human presequence protease (hPreP) agonists for the treatment of Alzheimer’s disease. European Journal of Medicinal Chemistry. Vol. 76, 2014, pp. 506 -€“ 516.

The summary of the Human Presequence Protease Agonist Library characteristics:

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