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Computational methods like molecular docking, pharmacokinetic study, molecular dynamic (MD) simulation and Molecular Mechanics‐Poisson‐Boltzmann Surface Area (MM‐PBSA) were used to investigate the ability of Glycyrrhiza glabra phytoconstituents to modulate the activity of GABA‐A receptor. The docking studies suggested that both Kanzonol U and Glabrol, have shown superior binding abilities, as evident by their binding energies of −11.8 and −11.4 kcal/mol, respectively, as compared to diazepam (−10.0 kcal/mol), which is an allosteric modulator of GABA‐A. Only nine constituents were identified as the blood‐brain barrier permeants in the SwissADME investigation, with binding energy≤−10.0 kcal/mol. The docking results were further strengthened by MD simulation which showed that the Kanzonol U and Glabrol complex displayed good conformational stability with an average RMSD of 0.20 nm. Additionally, MM‐PBSA outcomes revealed that these phytochemicals as the most potent GABA‐A modulators. All these investigations suggest that the phytochemicals Kanzonol U and Glabrol may produce a promising antiepileptic effect. [ABSTRACT FROM AUTHOR]

The most promising anticonvulsant phytocompounds were explored in this work using docking, molecular dynamic (MD) simulation, and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) approaches. A total of 70 phytochemicals were screened against α-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA), N -methyl-d-aspartate (NMDA), voltage-gated sodium ion channels (VGSC), and carbonic anhydrase enzyme II (CA II) receptors, and the docking results were compared to the reference drug phenytoin. Amentoflavone displayed the highest affinity for AMPA and VGSC receptors, with docking scores of - 10.4 and - 10.1 kcal/mol, respectively. Oliganthin H-NMDA and epigallocatechin-3-gallate-CA II complexes showed docking scores of - 10.9 and - 6.9 kcal/mol, respectively. All four complexes depicted a high dock score compared to the phenytoin complex at the binding site of the corresponding proteins. The MD simulation investigated the stabilities and favorable conformation of apoproteins and ligand/reference-bound complexes. The results revealed that proteins AMPA, VGSC, and CA II were more efficiently stabilized by lead phytochemicals than phenytoin binding. Additionally, principal component analysis and MM-PBSA results suggested that these lead phytocompounds have good compactness and strong binding free energy. Further, physicochemical and pharmacokinetic studies revealed that these final lead phytochemicals would be suitable for oral intake, have sufficient intestinal permeability, and have the ability to cross the blood-brain barrier (BBB). Comprehensively, this study predicted amentoflavone as the best lead phytochemical out of the 70 anticonvulsant phytocompounds that can be used to treat epilepsy., Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03948-1., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© King Abdulaziz City for Science and Technology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Computational investigation of orotate phosphoribosyltransferase (OPRT) action, an enzymatic reaction between phosphoribosyl pyrophosphate (PRPP) and orotic acid (OA) to yield orotidine 5'-monophosphate (OMP), was carried out. Insights into the pathways of the substrate attack step of the reaction were developed under the quantum mechanics/molecular mechanics framework with S. cerevisiae strain as the representative enzyme bearer. Four pathways were proposed for PRPP and OA binding differing in the sequence of PRPP, OA and Mg 2+ ion complexation with OPRT. The formation of Mg 2+ -OPRT complex was accompanied by a small energy change while the largest stabilization was observed for the formation of Mg 2+ -PRPP complex supporting the experimental observation of Mg 2+ -PRPP complex as the true substrate for the reaction. Formation of PRPP-OPRT complex was found to be energetically not probable rendering the pathway requiring Mg 2+ -OA complex not probable. Further, PRPP migration towards the active site was found to be energetically not favoured rendering the pathway involving Mg 2+ -OA complexation improbable. Migration of OA and Mg 2+ -PRPP complex towards the active site was found to be energetically probable with a large stabilization of the system when Mg 2+ -PRPP complex bound to the OA-OPRT complex. This conclusively proved the sequential binding of OA and Mg 2+ -PRPP complexes during OPRT action., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The role of Mg 2+ cofactor in orotate phosphoribosyltransferase (OPRT) catalyzed synthesis of orotidine monophosphate (OMP) from phosphoribosyl pyrophosphate (PRPP) and orotate (OA) in substrate binding and the influence of the identity of the divalent metal ion on the reaction mechanism were addressed in this study using quantum mechanics/molecular mechanics framework. Energetics of migration and binding of different substrate complexes in the active site cavity was established. A quantitative analysis of various processes indicated the reaction pathway to consist of complexation of Mg 2+ with PRPP, migration of Mg 2+ -PRPP and OA towards the active site, binding of OA to OPRT, and binding of Mg 2+ -PRPP complex to OA-OPRT complex. The mechanism of the reaction was unaltered by the change in the identity of divalent metal ion. Experimentally reported inhibiting character of Co 2+ was explained on the basis of large Co 2+ -PRPP binding and migration energies. Mg 2+ , Ca 2+ , Mn 2+ , Co 2+ and Zn 2+ ions were screened computationally to assess their inhibiting/activating characteristics. Trends obtained by our computational investigations were in correspondence with experimentally reported trends., (Copyright © 2018 Elsevier Ltd. All rights reserved.)