Docking-Based 3D-QSAR Studies for 1,3,4-oxadiazol-2-one Derivatives as FAAH Inhibitors

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.

Identifying FAAH Inhibitors as New Therapeutic Options for the Treatment of Chronic Pain through Drug Repurposing

“…A 3D-QSAR CoMSIA study was previously performed on 90 pyrimidinyl-piperazinecarboxamide derivatives that irreversibly inhibit FAAH and concluded that electrostatic and hydrogen-bond acceptor properties are the most important for the activity of these types of compounds [46]. Similar 3D-QSAR CoMFA and CoMSIA models were constructed for a series of 1,3,4-oxadiazol-2-one derivatives [50]. The importance of the 1,3,4-oxadiazol-2-one scaffold was revealed also in our study by the high P-PR value of fragment PR21.…”

Comparative Molecular Field Analysis (CoMFA), Molecular Docking and ADMET Study on Thiazolidine-4-carboxylic acid Derivatives as New Neuraminidase Inhibitors

“…One of the significant advantages of this approach is its immediate application in the examination of any structure-dependent biological characteristics. 22 The CoMFA theory states that differences in a target property between chemicals are frequently associated with changes in the noncovalent fields that surround those structures. These fields, which are the electrostatic (Coulombic) and steric (Lennard-Jones) fields, are computed at regular intervals within a predetermined area.…”

Molecular Modeling Studies of N-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3

“…The in-depth analysis process is described in the Supplementary Material under the Methodology Section. The progressive scrambling study was conducted as described in this study [49].…”