Industry Talk - Pharmacelera

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Speaker: Dr Beth Tuerk from Pharmacelera

Title: 3D Quantum Mechanics–Driven Hydrophobicity Descriptors to Navigate Chemical Spaces: Methodology and Applications of Field technology

Abstract: 

We present a QM-derived 3D molecular-field methodology, implemented in the PharmScreen® and exaScreen® platforms, in which quantum-mechanics-informed hydrophobicity and electrostatic interaction fields are used to align, compare, and mine molecules independently of scaffold, enabling meaningful comparisons from focused SAR series to libraries spanning billions of compounds.

We illustrate this through three applications.

Application 1:  In the CACHE#5 blind benchmark for Melanin-Concentrating Hormone Receptor 1 (MCHR1) antagonists, ligand-based screening of a~40-billion-compound version of the Enamine REAL space identified the most potent compound among 25 teams, including a scaffold hop (Tanimoto 0.27) and four compounds with pKi > 7, followed by SAR optimization achieving a 55% success rate.

Application2: together with Domainex, field similarity and growth-vector alignment guided reaction-aware fragment expansion within a Direct-to-Biology chemical space, yielding an analogue library with improved hit rate and ligand efficiency.

Application3:  In the highly conserved JAK kinase family, ligand-derived electrostatic and hydrophobic fields were used to regenerate and rescore docking poses, improving pose prioritization and selectivity analysis over conventional docking.