Abstract
This work aimed to construct 3D-QSAR CoMFA and CoMSIA models for a series of 31 FAAH inhibitors, containing the 1,3,4-oxadiazol-2-one moiety. The obtained models were characterized by good statistical parameters: CoMFA Q2 = 0.61, R2 = 0.98; CoMSIA Q2 = 0.64, R2 = 0.93. The CoMFA model field contributions were 54.1% and 45.9% for steric and electrostatic fields, respectively. In the CoMSIA model, electrostatic, steric, hydrogen bond donor, and hydrogen acceptor properties were equal to 34.6%, 23.9%, 23.4%, and 18.0%, respectively. These models were validated by applying the leave-one-out technique, the seven-element test set (CoMFA r2test-set = 0.91; CoMSIA r2test-set = 0.91), a progressive scrambling test, and external validation criteria developed by Golbraikh and Tropsha (CoMFA r20 = 0.98, k = 0.95; CoMSIA r20 = 0.98, k = 0.89). As the statistical significance of the obtained model was confirmed, the results of the CoMFA and CoMSIA field calculation were mapped onto the enzyme binding site. It gave us the opportunity to discuss the structure–activity relationship based on the ligand–enzyme interactions. In particular, examination of the electrostatic properties of the established CoMFA model revealed fields that correspond to the regions where electropositive substituents are not desired, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one moiety. This highlights the importance of heterocycle, a highly electronegative moiety in this area of each ligand. Examination of hydrogen bond donor and acceptor properties contour maps revealed several spots where the implementation of another hydrogen-bond-donating moiety will positively impact molecules’ binding affinity, e.g., in the neighborhood of the 1,3,4-oxadiazol-2-one ring. On the other hand, there is a large isopleth that refers to the favorable H-bond properties close to the terminal phenoxy group of a ligand, which means that, generally speaking, H-bond acceptors are desired in this area.
Highlights
The fatty acid amide hydrolase enzyme (FAAH) belongs to the serine hydrolase superfamily
We used 3D-QSAR techniques to examine the structure–activity relationship of a series of 1,3,4-oxadiazol-2-one compounds. Both constructed 3D-QSAR models were derived from a modeling set containing 31 compounds
They were evaluated using the same statistical methods, including the leave-one-out technique, prediction of pIC50 values for an external group of compounds, scrambling stability test, and additional external validation criteria presented by Golbraikh and Tropsha
Summary
The fatty acid amide hydrolase enzyme (FAAH) belongs to the serine hydrolase superfamily. It is involved in the degradation of biologically active lipids—endocannabinoids, e.g., anandamide and 2-arachidonoylglycerol—or related-amidated signaling lipids. FAAH activity is considered to play an essential role in the development of multiple pathological conditions [1]. Enzyme inhibitors may exhibit analgesic, anti-inflammatory, anxiolytic, and antidepressant activity. Blockade of FAAH does not cause undesirable side effects of direct cannabinoid agonists [2]. Its blockade became an emerging strategy in the treatment of several central nervous system (CNS) and peripheral diseases [1,2,3,4]. The development of novel effective FAAH inhibitors became a key focus in drug design [4,5]. A ligand that recently got into phase 1 of clinical trials resulted in the death of one healthy volunteer and led to some mild-to-severe neurological symptoms in others [6]
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