SKIN Pathophysiology library

The "SKIN Pathophysiology library" is a highly specialized, computationally curated collection of 2,126 chemical compounds designed for targeted screening against the molecular mechanisms underlying chronic inflammatory and autoimmune skin diseases.

This library represents an enriched set of molecules that are hypothesized to exhibit high potential activity against the defining targets of Psoriasis, Atopic Dermatitis (AD), and other major dermatoses.

Biological Rationale and Targeted Mechanisms

The design of the "SKIN Pathophysiology library" was fundamentally guided by the necessity to modulate the central, interconnected pathways of chronic skin inflammation. The library is optimized for identifying ligands against the following critical targets:

1. Master Regulators & Signal Transduction:

·       Tumor Necrosis Factor (TNF): The central cytokine driving chronic inflammation.

·       Nuclear Factor-κB (NF-κB): The universal transcription factor governing the inflammatory cascade.

·       The JAK-STAT Pathway (JAK1, JAK2, JAK3, TYK2): The key signaling axis for numerous cytokines involved in AD and Psoriasis.

·       Phosphodiesterase 4 (PDE4 & PDE4B): An enzyme that negatively regulates the anti-inflammatory messenger cAMP.

2. Inflammatory Effectors & Initiators:

·       Interleukin 17A (IL-17A): The dominant effector cytokine responsible for keratinocyte hyperproliferation in Psoriasis.

·       Prostaglandin-Endoperoxide Synthase 2 (PTGS2 / COX-2): The inducible enzyme responsible for producing pro-inflammatory prostaglandins.

·       Prostaglandin-Endoperoxide Synthase 1 (PTGS1 / COX-1): Contributing to the initial inflammatory burst and general homeostasis.

·       Interleukin 6 (IL-6) and Interleukin 1 Beta (IL-1β): Potent, early-phase pro-inflammatory cytokines.

·       NLRP3 Inflammasome: The complex sensor responsible for activating IL-1β and initiating sterile inflammation.

3. Immune Cell Trafficking:

• Sphingosine-1-phosphate receptor 1 (S1PR1): A crucial receptor regulating the egress and circulation of pathogenic lymphocytes.

Library Construction and Enrichment Methodology

The generation of the "SKIN Pathophysiology library" employed a rigorous, multi-step computational workflow to ensure chemical diversity, druggability, and biological relevance:

Step 1: Rigorous Chemical Curation and Filtering
The process began by filtering a vast initial chemical pool using stringent medicinal chemistry criteria. Compounds with undesirable characteristics were removed, including those prone to pan-assay interference (PAINS), molecules containing reactive or unstable moieties, and those predicted to have poor ADME (Absorption, Distribution, Metabolism, Excretion) or high toxicity profiles.

Step 2: Consensus Ligand-Based Virtual Screening
Following initial filtering, the collection was refined through a sophisticated ligand-based virtual screening campaign. This selection was driven by a set of well-characterized reference templates known to inhibit or modulate the dermatological targets listed above.

A comprehensive consensus approach was implemented to select only high-confidence candidates, integrating orthogonal similarity metrics:

• 2D & 3D Descriptor Similarity: Compounds were prioritized based on the closeness of their calculated physicochemical properties (e.g., molecular weight, polarity) and structural 3D characteristics to the reference templates.
• 2D Fingerprint Similarity: The structural connectivity of the molecules was encoded using binary fingerprints (e.g., ECFP4), and similarity (Tanimoto coefficient) was used to ensure candidates share core structural scaffolds with known active molecules.
• 3D Shape and Pharmacophore Similarity: This critical step assessed the spatial geometry and electrostatic complementarity of the molecules. Only those compounds capable of mimicking the critical three-dimensional volume and chemical feature arrangement (the pharmacophore) of the active templates were included.

By integrating these orthogonal assessments, the final 2,126 compounds were assembled, creating a highly enriched and structurally diverse collection optimized for discovering novel small-molecule modulators of skin disease pathways.