Friday, 1 April 2022

Enthalpic fragments

Enthalpy-driven binding has been presented as a rationale for screening fragments although some have argued that thermodynamic signature is actually a 'red herring' in the context of drug discovery.  Binding of a ligand grown from a fragment hit incurs a translational entropy penalty that is similar to that of the original fragment hit and it is therefore it is hardly surprising that synthetic elaboration results in binding that is more driven by entropy.

A recent collaborative study between researchers in the Budapest Enthalpomics Group (BEG) and Prof Wilhelmina Wiplasch, well known for her seminal study ‘The Ecstasy and Agony of Recreational PAINS’, shows this view to be hopelessly naïve. The mathematical treatment used in the study is formidable and was originally developed by Prof Wiplasch during a sabbatical at the Port-au-Prince Institute of Biogerontology. Briefly, deep learning was used to model the time-dependent covariance and kurtosis of the polarizability tensor for a series of rhodanines, showing that the enthalpic nature of fragment binding is caused by their greater ligand efficiencies. “This model comprehensively outperforms all competitors”, explains Group Leader Prof Kígyó Olaj, “and we have shown for the very first time that the Sackur-Tetrode equation can be safely consigned to the dustbin of History”.