Transmembrane protein 175 (TMEM175) Library

Transmembrane protein 175 (TMEM175) is a critical lysosomal ion channel gaining significant attention as a therapeutic target. Located primarily in the membranes of late endosomes and lysosomes, TMEM175 functions as a K+ leak channel and also facilitates proton transport. This activity is crucial for maintaining lysosomal pH homeostasis and overall lysosomal function, processes vital for cellular health and degradation pathways.

Emerging scientific evidence strongly links TMEM175 function and dysfunction to human health and disease. It plays a key role in regulating lysosomal pH, and its genetic variants are associated with an increased risk of Parkinson's disease (PD). Modulation of TMEM175 activity presents a novel therapeutic strategy for PD and potentially other neurodegenerative disorders or diseases linked to lysosomal dysfunction. Despite its growing importance and validation as a target, there are currently no approved drugs on the market that specifically target TMEM175, highlighting a significant unmet medical need and a valuable opportunity for drug discovery.

This library was constructed using a sophisticated, multi-step in silico screening approach starting from ChemDiv's diverse 1.6 million compound collection:

Initial Filtering: Application of medicinal chemistry filters (MCF), including PAINs (Pan-Assay Interference Compounds) and REOS (Rapid Elimination Of Swill), to remove compounds with undesirable structural features.

Similarity & Scaffold Hopping: 2D similarity searching based on known active agents or initial hits was employed to identify structurally related molecules within the filtered set.

Topological & Diversity Analysis: 2D topology analysis (computing connectivity, branching, shape-encoding descriptors) and broader descriptor space analysis (constitutional, physicochemical, topological) were performed to ensure structural diversity and select compounds with favorable features.

QSAR Modeling: Iteratively developed Quantitative Structure-Activity Relationship (QSAR) models were applied to predict the biological activity of the selected compounds against TMEM175 based on their structural descriptors, refining the collection to the final ~7,000 compounds.

Target-Focused: Computationally enriched for compounds predicted to interact with TMEM175.

Chemically Diverse: The library features a broad range of distinct chemotypes, enhancing the probability of discovering novel hit series (as illustrated by t-SNE clustering and example structures).

Drug-Like Properties: Compounds were selected based on favorable physicochemical profiles, including molecular weight, polarity (PSA), lipophilicity (LogP), hydrogen bonding capacity (HBD/HBA), rotatability, predicted solubility (LogSw), and drug-likeness (QED), aiming for better downstream developability.

Foundation for Advancement: While virtual, the selection strategy draws parallels with approaches that have yielded compounds progressing to biological testing and preclinical stages (as indicated by R&D data on related small molecules).

ChemDiv's TMEM175 Focused Virtual Library provides researchers with a high-quality, diverse, and computationally validated starting point for identifying novel modulators of this important lysosomal channel. This resource can significantly accelerate hit identification efforts in the pursuit of first-in-class therapeutics for Parkinson's disease and other disorders associated with lysosomal dysfunction.