Abstract
Numerous empirical scoring schemes are arbitrary, yielding contradictory results for different protein inhibitor families. This study is aimed to validate the predictive potential of alternative nonempirical model of inhibitory activity based on first principle quantum chemical results for new class of small molecules targeting the menin-mixed lineage leukemia (MLL) interaction. Presented nonempirical interaction energy model comprising long-range electrostatic multipole and approximate dispersion terms is universal and computationally affordable, outperforming a number of commonly used empirical scoring functions, especially when combined with analysis of solvation energy.
Highlights
Computational methods used to estimate the inhibitory activity are mostly based on arbitrary empirical scoring functions or force fields that provide rather differing estimates [1, 2]
[14], we have demonstrated that menin-mixed lineage leukemia (MLL) inhibitors can be successfully described with nonempirical model based on the long-range components of the interaction energy, namely multipole electrostatic and approximate dispersion
The set of inhibitors studied appears to be challenging in terms of obtaining the proper ligand ranking, as most of the empirical scoring functions tested currently were capable of providing at least the qualitative estimates of the inhibitory activity of thienopyrimidine class of menin-MLL inhibitors [14]
Summary
Computational methods used to estimate the inhibitory activity are mostly based on arbitrary empirical scoring functions or force fields that provide rather differing estimates [1, 2]. More accurate quantum chemical predictions are impractical in virtual high-throughput screening of drug candidates due to their significant computational cost, and their applicability to protein–ligand interactions has been rather limited [3, 4]. Simplified nonempirical models for the description of inhibitory activity are needed. They can be derived from the systematical partitioning of the ab initio computed interaction energy into welldefined contributions, yielding approximate nonempirical yet affordable models of general applicability. Published as part of the special collection of articles In Memoriam of János Ángyán. This paper is dedicated to the memory of János G.
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