Computational investigation of pyrrolidin derivatives as novel GPX4/MDM2–p53 inhibitors using 2D/3D-QSAR, ADME/toxicity, molecular docking, molecular dynamics simulations, and MM-GBSA free energy

Tabti, Kamal; Baammi, Soukayna; Elmchichi, Larbi; Sbai, Abdelouahid; Maghat, Hamid; Bouachrine, Mohammed; Lakhlifi, Tahar

doi:10.1007/s11224-022-01903-5

Cited by 22 publications

(15 citation statements)

References 45 publications

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“…To measure docking accuracy, the RMSD of heavy atoms between the docked poses and the crystallographic poses of the ligand (NAD + ) was calculated 22 . A molecular docking protocol is reliable if the root-mean-square deviation (RMSD) is less than 2 Å 23 .…”

Section: Methodsmentioning

confidence: 99%

In silico protein engineering shows that novel mutations affecting NAD+ binding sites may improve phosphite dehydrogenase stability and activity

Baammi

Daoud

Allali

2023

Sci Rep

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Pseudomonas stutzeri phosphite dehydrogenase (PTDH) catalyzes the oxidation of phosphite to phosphate in the presence of NAD, resulting in the formation of NADH. The regeneration of NADH by PTDH is greater than any other enzyme due to the substantial change in the free energy of reaction (G°′ = − 63.3 kJ/mol). Presently, improving the stability of PTDH is for a great importance to ensure an economically viable reaction process to produce phosphite as a byproduct for agronomic applications. The binding site of NAD+ with PTDH includes thirty-four residues; eight of which have been previously mutated and characterized for their roles in catalysis. In the present study, the unexplored twenty-six key residues involved in the binding of NAD+ were subjected to in silico mutagenesis based on the physicochemical properties of the amino acids. The effects of these mutations on the structure, stability, activity, and interaction of PTDH with NAD+ were investigated using molecular docking, molecular dynamics simulations, free energy calculations, and secondary structure analysis. We identified seven novel mutations, A155I, G157I, L217I, P235A, V262I, I293A, and I293L, that reduce the compactness of the protein while improving PTDH stability and binding to NAD+.

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Section: Methodsmentioning

confidence: 99%

In silico protein engineering shows that novel mutations affecting NAD+ binding sites may improve phosphite dehydrogenase stability and activity

Baammi

Daoud

Allali

2023

Sci Rep

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“…The docked poses were minimized using the local optimization feature in Prime, and the binding free energies of the complexes were calculated using the Molecular Mechanics/Generalized Born Surface Area (MM‐GBSA) continuum solvent model, which incorporates the OPLS‐2005 force field, [38,39] VSGB solvent model, [40] and rotamer search algorithms from Prime (v3.1, Schrödinger 2021–3). To remove false positives obtained from the molecular docking analysis, the generalized Born surface method of molecular mechanics (MM/GBSA) was used to calculate the binding free energy for each compound [41] .…”

Section: Binding Free Energy Estimation Using Prime/mm‐gbsa Methodsmentioning

confidence: 99%

“…Moreover, a re-docking of the co-crystallized ligand was performed in the same binding pocket to justify the reliability of the applied docking method. [38] Figure 3. Colchicine binding site (PDB 1SA0) co-crystal structure asteroid plots, The inner shell residues were those that had direct contact with the ligand molecule, whereas the outer shell residues were those that had indirect interactions with the ligand.…”

Section: Receptor Grid Generation and Molecular Dockingmentioning

confidence: 99%

“…The Precision Additional Protocol (XP) of the GLIDE tool was applied, considering the receptor as a rigid entity and the ligands as flexible to identify the most favorable interaction profile with the residues in the colchicine binding pocket. Moreover, a re‐docking of the co‐crystallized ligand was performed in the same binding pocket to justify the reliability of the applied docking method [38] …”

Section: Receptor Grid Generation and Molecular Dockingmentioning

confidence: 99%

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Computational Exploration of the Structural Requirements of Triazole Derivatives as Colchicine Binding Site Inhibitors

et al. 2023

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Colchicine inhibits microtubule assembly by preventing tubulin polymerization, making the colchicine binding site a promising target against cancer. The present study focuses on the 3D‐QSAR analysis of 31 triazole analogs. The atom‐based and field‐based QSAR models exhibit significant statistical results for internal and external validations, with the atom‐based 3D‐QSAR model showing a Q2 of 0.658 and R2 of 0.998, and the field‐based 3D‐QSAR model showing a Q2 of 0.658 and R2 of 0.998. The 3D‐QSAR atom‐based pharmacophore model explains biological activity using a six‐point hypothesis (AHHRRR.1), while the field‐based 3D‐QSAR model explains activity based on steric, electrostatic, hydrophobic, and hydrogen bond donor/acceptor fields. Based on the 3D contour maps generated, five new compounds were designed and their ADME/Tox properties predicted. The results suggested that these compounds possess potent pharmacological characteristics. The results of the molecular docking analysis showed that Pred01 and Pred02 had higher docking scores (−6.2417Kcal/mol and −6.5049Kcal/mol, respectively) than compound 15, and they formed notable hydrogen bonds and hydrophobic interactions with active site residues. The MMGBSA results confirmed these findings and emphasized the essential role of van der Waals energy in the binding energy. Moreover, the dynamic stability of the complexes was further supported by MD simulations.

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“…where x, y, and z are the coordinates of the i atoms of the pose and the reference nucleotide (ref). [43] Unless explicitly stated, RMSD calculations are performed on all heavy atoms except for atoms except for the oxygen atoms of the phosphate group which have been discarded for reasons of symmetry reasons. Overall, a pose was considered to reproduce the interaction mode if its RMSD had a value less than or equal to 2 Å.…”

Section: Docking Protocolmentioning

confidence: 99%

Quality Control of Coumarins, Furocoumarins and Polymethoxyflavones in Citrus Essential Oils: In Silico Analysis

Ouabane.,

Alaqarbeh,

Hajji

et al. 2024

ChemistrySelect

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Citrus essential oils (EOs) contain a variety of secondary metabolites, including coumarins (Cs), furocoumarins (FCs) and polymethoxyflavones (PMFs), all with different biological activities. While Regulation (EC) No 1334/2008 strictly regulates the use of coumarins, undesirable side effects of consuming furocoumarins remain without established maximum toxicity limits for human dietary intake. This study is based on an in‐silico approach aimed at determining these toxicity limits for the oxygenated heterocyclic compounds of citrus EOs approved for use in food. In addition, an innovative quantitative structure‐property relationship (QSPR) using the linear retention index system was explored to characterize the oxygenated heterocyclic compounds (COHs) present in these essential oils. Molecular docking of the studied compounds provided crucial insights into the structure‐odor relationships, offering insights into their mechanisms of action. In addition, an analysis of the pharmacokinetic and pharmacodynamic properties through ADME‐Tox deconstruction provides insight into the potential side effects of their consumption. The results are consolidated by dynamic simulations, providing crucial data for the development of regulations on the maximum toxicity limits of citrus EOs, given the health implications of the various compounds such as coumarins, furocoumarins and polymethoxyflavones present in these essential oils.

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Computational investigation of pyrrolidin derivatives as novel GPX4/MDM2–p53 inhibitors using 2D/3D-QSAR, ADME/toxicity, molecular docking, molecular dynamics simulations, and MM-GBSA free energy

Cited by 22 publications

References 45 publications

In silico protein engineering shows that novel mutations affecting NAD+ binding sites may improve phosphite dehydrogenase stability and activity

In silico protein engineering shows that novel mutations affecting NAD+ binding sites may improve phosphite dehydrogenase stability and activity

Computational Exploration of the Structural Requirements of Triazole Derivatives as Colchicine Binding Site Inhibitors

Quality Control of Coumarins, Furocoumarins and Polymethoxyflavones in Citrus Essential Oils: In Silico Analysis

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