Abstract
Halogenated ligands are nowadays commonly designed in order to increase their potency against protein targets. Although novel computational methods of evaluating the affinity of such halogenated inhibitors have emerged, they still lack the sufficient accuracy, which is especially noticeable in the case of empirical scoring functions, being the method of choice in the drug design process. Here, we evaluated a series of halogenated inhibitors of phosphodiesterase type 5 with ab initio methods, revealing the physical nature of ligand binding and determining the components of interaction energy that are essential for proper inhibitor ranking. In particular, a nonempirical scoring model combining long-range contributions to the interaction energy provided a significant correlation with experimental binding potency, outperforming a number of commonly used empirical scoring functions. Considering the low computational cost associated with remarkable predictive abilities of the aforementioned model, it could be used for rapid assessment of the ligand affinity in the process of rational design of novel halogenated compounds.
Highlights
It has been recognized that halogen compounds interact with atoms possessing a lone electron pair (Lewis base, e.g., O, N, S atoms or π -electron systems) through so called halogen bonding, where the halogen atom acts as an acceptor (Lewis acid) [1,2,3]
A set of 5 phosphodiesterase type 5 (PDE5) inhibitors developed by Xu et al [31] is examined with ab initio and empirical methods to analyze the effect of the halogen substitution on the binding affinity
PDE5 binding site model considered includes 11 amino acid residues surrounding the inhibitor in the vicinity of 5 Awithin the atom occupying pyrimidinone 5-position (Fig. 2)
Summary
It has been recognized that halogen compounds (iodine, bromine, chlorine or even, to some extent, fluorine) interact with atoms possessing a lone electron pair (Lewis base, e.g., O, N, S atoms or π -electron systems) through so called halogen bonding, where the halogen atom acts as an acceptor (Lewis acid) [1,2,3]. Halogen bonding is related to the anisotropy of the electron density and the emergence of increased electrostatic potential, i.e., σ -holes [4, 5]. This electrostatically driven, directional, intermolecular interaction [6] has been successfully exploited in the drug development process [7,8,9,10], and is often found in biomolecular. Taking advantage of the long-range interaction energy terms including electrostatic atomic multipole expansion (EE(1L0),MT P ) and approximate dispersion function (EDas), it constitutes a low cost approach that can be used in various biomolecular systems.
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