Physical Nature of Fatty Acid Amide Hydrolase Interactions with Its Inhibitors: Testing a Simple Nonempirical Scoring Model

Abstract

Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the deactivating hydrolysis of fatty acid ethanolamide neuromodulators. FAAH inhibitors have gained considerable interest due to their possible application in the treatment of anxiety, inflammation, and pain. In the context of inhibitor design, the availability of reliable computational tools for predicting binding affinity is still a challenging task, and it is now well understood that empirical scoring functions have several limitations that in principle could be overcome by quantum mechanics. Herein, systematic ab initio analyses of FAAH interactions with a series of inhibitors belonging to the class of the N-alkylcarbamic acid aryl esters have been performed. In contrast to our earlier studies of other classes of enzyme-inhibitor complexes, reasonable correlation with experimental results required us to consider correlation effects along with electrostatic term. Therefore, the simplest comprehensive nonempirical model allowing for qualitative predictions of binding affinities for FAAH ligands consists of electrostatic multipole and second-order dispersion terms. Such a model has been validated against the relative stabilities of the benchmark S66 set of biomolecular complexes. As it does not involve parameters fitted to experimentally derived data, this model offers a unique opportunity for generally applicable inhibitor design and virtual screening.

Are Various σ‐Hole Bonds Steered by the Same Mechanisms?

“…modeled 66 biomolecular complexes based on the complete electrostatic term EL or its long‐range electrostatic multipole component EL,MTP, which display low sensitivity to docking errors, in contrast to corresponding high‐level MP2 or CCSD(T)/CBS results. Supplementing the EL,MTP term with another long‐range correlation term, CORR, results in a more universal model that is able to give relative stability predictions for systems that involve hydrophobic interactions . Replacement of the CORR term by dispersion functions, Das, gives simple universal EL,MTP+Das model scaling as O(A 2 ), which has been successfully applied in nonempirical scoring of inhibitor–receptor interactions for fatty‐acid amide hydrolase inhibitors …”

“…Supplementing the EL,MTP term with another long‐range correlation term, CORR, results in a more universal model that is able to give relative stability predictions for systems that involve hydrophobic interactions . Replacement of the CORR term by dispersion functions, Das, gives simple universal EL,MTP+Das model scaling as O(A 2 ), which has been successfully applied in nonempirical scoring of inhibitor–receptor interactions for fatty‐acid amide hydrolase inhibitors …”

Revisiting the halogen bonding between phosphodiesterase type 5 and its inhibitors

“…Overall, the performance of scoring functions appear to be different depending on the system studied [23] and there is no apparent choice of an appropriate scoring approach to be used with a certain protein-ligand system. However, our nonempirical model has been shown to possess the satisfactory predictive abilities for a variety of enzyme-inhibitor complexes [20, 21] including the PPI inhibitors [22, 23, 33]. Our current results seem to extend the range of application of model to halogen-bearing compounds.…”

“…As already emphasized, the performance of the approximate model, accounting for long-range interaction energy terms only, is comparable to the predictive capabilities of E M P 2 binding energy. However, the computational cost of model is equivalent to force field calculations [20], as it scales with the square number of atoms, O ( A 2 ), while computational scaling of E M P 2 energy is described by the fifth power of the number of atomic orbitals, O ( N 5 ).…”

Application of a simple quantum chemical approach to ligand fragment scoring for Trypanosoma brucei pteridine reductase 1 inhibition

“…An example is the finding that for polar or charged inhibitors of phenylalanine ammonia-lyase and leucine aminopeptidase, the nonempirical first-order electrostatic interaction energy defined within perturbation theory [ 5 ] (or its multipole component [ 6 ]) alone yielded a reasonable correlation with experimental inhibitory activity data. However, such a simple model is insufficient for nonpolar receptors, like fatty acid amide hydrolase (FAAH), where inclusion of a nonempirical dispersion term, in addition to the electrostatic multipole term, was necessary to describe inhibitory activities [ 7 ]. Likewise, as noted by Lonsdale et al [ 8 ], dispersion effects should be considered for reliable modeling of enzyme-catalyzed reactions.…”