Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Abstract

Aim: To identify the critical chemical features, with reliable geometric constraints, that contributes to the inhibition of butyrylcholinesterase (BChE) function. Methods: Ligand-based pharmacophore modeling was used to identify the critical chemical features of BChE inhibitors. The generated pharmacophore model was validated using various techniques, such as Fischer's randomization method, test set, and decoy set. The best pharmacophore model was used as a query in virtual screening to identify novel scaffolds that inhibit BChE. Compounds selected by the best hypothesis in the virtual screening were tested for drug-like properties, and molecular docking study was applied to determine the optimal orientation of the hit compounds in the BChE active site. To find the reactivity of the hit compounds, frontier orbital analysis was carried out using density functional theory. Results: Based on its correlation coefficient (0.96), root mean square (RMS) deviation (1.01), and total cost (105.72), the quantitative hypothesis Hypo1 consisting of 2 HBA, 1 Hy-Ali, and 1 Hy-Ar was selected as the best hypothesis. Thus, Hypo1 was used as a 3D query in virtual screening of the Maybridge and Chembridge databases. The hit compounds were filtered using ADMET, Lipinski's Rule of Five, and molecular docking to reduce the number of false positive results. Finally, 33 compounds were selected based on their critical interactions with the significant amino acids in BChE's active site. To confirm the inhibitors' potencies, the orbital energies, such as HOMO and LUMO, of the hit compounds and 7 training set compounds were calculated. Among the 33 hit compounds, 10 compounds with the highest HOMO values were selected, and this set was further culled to 5 compounds based on their energy gaps important for stability and energy transfer. From the overall results, 5 hit compounds were confirmed to be potential BChE inhibitors that satisfied all the pharmacophoric features in Hypo1. Conclusion: This study pinpoints important chemical features with geometric constraints that contribute to the inhibition of BChE activity. Five compounds are selected as the best hit BchE-inhibitory compounds.

Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling

“…The moderately active and inactive compounds exhibited high energy gaps that were not suitable for the reactivity of the molecules. Our results were consistent with published research in the literature [19,28,29] . Thus, the DFT results indicated that the hit compounds have equivalent or greater electronic properties than most of the active compounds.…”

“…Similarly, the compounds of the test set were also classified based on their activities. The 2D chemical structures of all compounds were drawn using ChemSketch [19] and were subsequently exported to Discovery Studio v3.5 (DS) for the generation of their corresponding 3D structures.…”

“…Most chemical reactions of a molecule are governed by these orbitals. The energy of the highest occupied molecular orbitals (HOMO) is directly related to the ionization potential (electron donor), whereas the lowest unoccupied molecular orbitals (LUMO) are related to the electron affinity (electron acceptor) [19,28,29] . The HOMO and LUMO are indicators of the possible electrophilic and nucleophilic attack sites in the molecules, respectively.…”

“…In this study, the HOMO and LUMO energies were calculated using four active, two moderately active, and one inactive compound from the training set as well as the 30 npg that the HOMO energy may promote the transfer of electrons from the HOMO of the inhibitor to residues in the active site of AKR1B10. A higher energy value of the HOMO in a compound corresponds to greater activity [19,28] . Only five hit compounds showed higher HOMO values than the already known inhibitors (Table 4).…”

Determinación del nivel de colinesterasa sérica en una población ocupacionalmente expuesta a plaguicidas en el municipio Zona Bananera, Magdalena (Colombia), 2012

“…Tanto los organofosforados como los carbamatos inhiben las dos colinesterasas, que tienen similitudes en su estructura, pero localizaciones y funciones distintas [13,14]. Según el sustrato sobre el que actúan y su inhibidor, son clasificadas en dos subfamilias: las acetilcolinesterasas o colinesterasas verdaderas presentes en sistema nervioso central y periférico, músculo y eritrocitos [13]; y las butirilcolinesterasas, conocidas también como pseudocolinesterasas o colinesterasas plasmáticas producidas en hígado y secretadas en el plasma, que además se hallan en músculo liso y adipocitos [6,14,13].…”