Theoretical Model of EphA2-Ephrin A1 Inhibition

Abstract

This work aims at the theoretical description of EphA2-ephrin A1 inhibition by small molecules. Recently proposed ab initio-based scoring models, comprising long-range components of interaction energy, is tested on lithocholic acid class inhibitors of this protein–protein interaction (PPI) against common empirical descriptors. We show that, although limited to compounds with similar solvation energy, the ab initio model is able to rank the set of selected inhibitors more effectively than empirical scoring functions, aiding the design of novel compounds.

Validation of approximate nonempirical scoring model for menin-mixed lineage leukemia inhibitors

“…Since theoretical models applied herein are restricted to the enthalpic contribution to the binding free energy, their performance is limited to the analysis of compounds with similar solvation energy. According to our recent results obtained for protein-protein inhibitors targeting EphA2-ephrin A1 interaction [15], large differences in the ligand solvation energy limit the applicability of the nonempirical models tested herein. On the other hand, roughly comparable values of solvation free energy of inhibitors, as demonstrated by relatively low standard deviation of G solv values, appear to ensure that the nonempirical models operating on the basis of enthalpic contribution provide reasonable inhibitory activity estimates.…”

“…Thus, all compounds possessing R3 substituents (compounds 18-26) were modeled on the basis of compound 27 (MI-503). The remaining inhibitors (11)(12)(13)(14)(15)(16)(17) were modeled on the basis of compound 9 (MI-136).…”

“…Similar analysis of EphA2-ephrin A1 inhibitors [15], another class of compounds targeting protein-protein Published as part of the special collection of articles In Memoriam of János Ángyán. This paper is dedicated to the memory of János G. Ángyán. interaction, has revealed that nonempirical models based on enthalpic contributions to the binding energy are limited to the sets of inhibitors with similar values of the solvation free energy, G solv . The initial G solv calculations have shown that our model cannot be applied to the full set of inhibitors, and therefore, we have finally selected only those compounds, whose solvation energy is comparable.…”

Revisiting the halogen bonding between phosphodiesterase type 5 and its inhibitors

“…As the QM-based methods are too computationally demanding to be applied in the drug design process [ 3 , 17 ], reliable and fast scoring approaches are needed. Our non-empirical function [ 20 ], already validated with various protein-ligand complexes [ 21 – 23 ], might appear useful. Taking advantage of the long-range interaction energy terms including electrostatic atomic multipole expansion ( ) and approximate dispersion function ( E D a s ), it constitutes a low cost approach that can be used in various biomolecular systems.…”

“…Our recent findings [ 23 , 33 ] suggest that interaction energy calculations should be accompanied by assessment of the solvation effects, since the considerable differences in the solvation free energy might affect the inhibitory activity ranking produced by herein applied theoretical models. As the latter account only for the enthalpic contribution to the binding free energy, their applicability requires consistency of free energy of solvation (Δ G s o l v ) among the analyzed set of inhibitors.…”