Virtual screening of molecules from Brazilian natural products with key characteristics for TMEM176B inhibition

The target of this study is TMEM176B, an ion channel protein expressed in immune cells and linked to biological pathways involving oncogenes, tumor suppression, and biomarkers. The objective of this study was to identify natural compounds with potential biological activity against TMEM176B using virtual screening from the NuBBE-DB database, processed with AutoDockGPU. The screening protocol was tailored to the protein’s characteristics, considering the hydrophobic limits of the lipid bilayer, binding affinity, ligand efficiency, and molecular interactions (evaluated with BINANA). ADME-Tox simulations (Absorption, Distribution, Metabolism, Excretion, and Toxicity) were conducted using SwissADME, pkCSM, ADMETLab, ProTox 3, and PHARMIT. Key ADME-Tox parameters included: (a) Absorption: water solubility, Caco-2 permeability, human intestinal absorption, skin permeability, and interaction with P-glycoprotein (as substrate and inhibitor). (b) Distribution: steady-state volume of distribution (VDss), fraction unbound in plasma, blood-brain barrier penetration, and CNS permeability. (c) Metabolism: as substrate (CYP2D6, CYP3A4) and inhibitor (CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4). (d) Excretion: total clearance and renal elimination via OCT2 substrate. (e) Toxicity: AMES toxicity, hepatotoxicity, cardiotoxicity, mutagenicity, genotoxicity, carcinogenicity, cytotoxicity, mitochondrial toxicity, nephrotoxicity, CNS and respiratory toxicity, skin sensitization, acute oral toxicity, and environmental toxicity in Tetrahymena pyriformis and Pimephales promelas. Compounds from various chemical classes—amino acids, peptides, carbohydrates, flavonoids, chalcones, lignoids, lipids, polyketides, phenylpropanoids, tannins, and terpenes—were evaluated. By applying these pharmacokinetic and toxicity filters together with the above mentioned screening ones, several candidate molecules with potential affinity for TMEM176B were identified. Among them, NuBBE_642 showed a promising profile. This compound, along with other top candidates, will be further investigated with molecular dynamics simulations to analyze their stability and interactions with TMEM176B. These findings represent a significant start point, as they support future structure-based optimization of these hits for potential therapeutic development.

This work was supported by FAPESP (Grant number: 2023/01920-8), CNPq (CABBIO - Grant number: 423717/2021-9) and CAPES.