Chemoinformatics Analyses of Tau Ligands Reveal Key Molecular Requirements for the Identification of Potential Drug Candidates against Tauopathies

Abstract

Tau is a highly soluble protein mainly localized at a cytoplasmic level in the neuronal cells, which plays a crucial role in the regulation of microtubule dynamic stability. Recent studies have demonstrated that several factors, such as hyperphosphorylation or alterations of Tau metabolism, may contribute to the pathological accumulation of protein aggregates, which can result in neuronal death and the onset of a number of neurological disorders called Tauopathies. At present, there are no available therapeutic remedies able to reduce Tau aggregation, nor are there any structural clues or guidelines for the rational identification of compounds preventing the accumulation of protein aggregates. To help identify the structural properties required for anti-Tau aggregation activity, we performed extensive chemoinformatics analyses on a dataset of Tau ligands reported in ChEMBL. The performed analyses allowed us to identify a set of molecular properties that are in common between known active ligands. Moreover, extensive analyses of the fragment composition of reported ligands led to the identification of chemical moieties and fragment combinations prevalent in the more active compounds. Interestingly, many of these fragments were arranged in recurring frameworks, some of which were clearly present in compounds currently under clinical investigation. This work represents the first in-depth chemoinformatics study of the molecular properties, constituting fragments and similarity profiles, of known Tau aggregation inhibitors. The datasets of compounds employed for the analyses, the identified molecular fragments and their combinations are made publicly available as supplementary material.

Explainable Fragment‐Based Molecular Property Attribution

“…The fragment combination strategy has also been validated to effectively start points for the development of novel drug compounds. [ 39 ] Specifically, the combination strategy always results in two different cases: the first is regarded as accurate attribution. As shown in Figure 2C, the top‐0, top‐1, and top‐2 attribution fragments on the first molecule form the “Ground Truth” fragment.…”

“…To experiment with local similarity analysis, we use Recap [ 41 ] fragmentation algorithm. In order to preprocess the fragments of the data molecules, we applied the same setting as Pinzi et al in the analyses, [ 39 ] i.e., we discarded these fragments with atoms outside the range of 5–55, and present in less than three molecules was removed. Meanwhile, duplicate structures derived by fragmentation of different compounds were also removed.…”

“…Overall, the identification of key structural fragments and molecular properties required to achieve high potency will significantly facilitate drug repurposing and the discovery of next‐generation drug candidates. [ 39 ] As the most critical application, our method can effectively localize key fragment structures on tasks that affect a specific property. Lead compound identification is a necessary drug discovery process that identifies or creates a compound that can interact with the selected target.…”

“…Overall, the identification of key structural fragments and molecular properties required to achieve high potency will significantly facilitate drug repurposing and the discovery of next-generation drug candidates. [39] As the most critical application, our method The results of "Top-k fragments" are the average of the differences with top-k attribution fragments. Higher results indicate more favorable to the property task; b) The bold value represents the maximum difference value when selecting k under the current task, that is, selecting the top-k attribution fragment is more effective and has the smallest bias.…”

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule regulation

“…We further investigated whether PHOX compounds might possess molecular properties and scaffolds required for tau anti-aggregation activity (Pinzi et al, 2021). The vast majority of the PHOX compounds met these requirements, with the exception of the bulkier benzylbenzene derivatives PHOX 9, 12, 16, and 19.…”