Small Molecule Docking Against Laminin Receptor 37LR
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Solution Overview
Problem
Current methods for treating prostate cancer and osteoarthritis lack effective small molecules that can interfere with the binding between laminin receptor (67LR/37LR) and pigment epithelium-derived factor (PEDF), and existing therapies for osteoarthritis are limited by the instability and size of PEDF, necessitating the identification of smaller, more stable molecules with anti-cancer and anti-inflammatory properties.
Innovation Solution
A method involving in silico docking of compound libraries against the 37LR crystal structure to identify compounds with predicted binding scores, followed by in vitro validation using the Maybridge Hitfinder library, specifically [4-(9h-fluoren-9-yl)piperazino](6-fluoro-4h-1,3-benzodioxin-8-yl)methanone (HTS07944SC) or its derivatives, to interfere with the 37LR and PEDF interaction, and assess their anti-cancer and anti-inflammatory effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PEDF is used as a therapeutic molecule to target laminin receptor, then anti-cancer and anti-inflammatory effects are achieved, but the molecule is too large and unstable at 25°C
Solution Approach 1:
The patent extracts the essential binding function of PEDF from its full protein structure and encapsulates it in a small molecule compound (Formula 1) that mimics PEDF's interaction with laminin receptor. This extracted functional unit is significantly smaller and more stable while retaining therapeutic activity.
Solution Approach 2:
The patent changes the physical and chemical parameters of the therapeutic agent by transforming PEDF (a large protein) into a small molecule compound with modified molecular weight, stability, and binding characteristics. The compound maintains PEDF's biological activity while improving stability at physiological temperatures.
2Productivity
If in silico docking is used to screen compounds against 37LR, then compound identification is accelerated and costs are reduced, but validation requires in vitro testing
Solution Approach 1:
The patent performs in silico docking and virtual screening before actual laboratory testing to pre-identify and prioritize compounds. This preliminary computational action filters and directs subsequent in vitro validation efforts, making the overall process more efficient and cost-effective.
3Productivity
If high-throughput screening is used to test thousands of compounds, then compound discovery is accelerated, but the hit rate is low (1% or less) and costs are high
Solution Approach 1:
The patent creates computational models (in silico docking) that replicate and predict binding interactions before physical testing. This virtual copying allows evaluation of compound binding affinity without actual laboratory experimentation, enabling broader screening with higher effective hit rates.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The identified compounds, such as [4-(9h-fluoren-9-yl)piperazino](6-fluoro-4h-1,3-benzodioxin-8-yl)methanone, demonstrate significant anti-cancer activity by inhibiting cell viability and anti-inflammatory effects by downregulating inflammatory genes and upregulating cartilage-specific genes, offering potential therapeutic benefits for prostate cancer and osteoarthritis.
Implementation Method 1
docking a compound library against the 37LR crystal structure; generating a plurality of compounds with predicted docking scores
Implementation Method 2
37/67 LR is a strong clinical correlate for progression, aggression, and chemotherapeutic relapse of several cancers including breast, prostate, and colon. The ability of 37/67 LR to promote cancer cell aggressiveness is further increased by its ability to transduce physiochemical and mechanosensing signals
Implementation Method 3
In joints, when PEDF (pigment epithelial derived factor) bind to laminin receptors (LR), it has anti-inflammatory, pro-chondrogenic and anti-angiogenic characteristics
Data Source
AI summary
An in silico screening method generated compounds that are against laminin receptor 37LR and their anti-cancer functions in prostate cancer cell lines are disclosed herein. A group of derivatives based on the hit compound from the in silico screening are synthesized and tested with improved IC50 value that can have relevant clinical use for prostate cancer or osteoarthritis.