Assessing the effect of a series of mutations on the dynamic behavior of phosphite dehydrogenase using molecular docking, molecular dynamics and quantum mechanics/molecular mechanics simulations

Baammi, Soukayna; Daoud, Rachid; Allali, Achraf El

doi:10.1080/07391102.2022.2064912

Cited by 9 publications

(6 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It shows conformational changes over time and allows us to determine whether the target-ligand complex is stable or not 25 . In the present study, the best scoring docked complexes of the best mutants were included as primary coordinates to check their stability during 100 ns simulation using GROMACS (version 2019.3) 13 with Charm 27 force field 26 . Each complex was solvated in a dodecahedron box (1.0 nm) with TIP3P water model before neutralization in the system with the counter ions 27 .…”

Section: Methodsmentioning

confidence: 99%

“…The mechanism of such alterations behind a mutation is being explored to better understand their effect on PTDH structure, stability, and activity 11 , 12 . Recently, we investigated how a series of mutations in P. stutzeri applied in the laboratory and deposited in the Brenda database ( https://www.brenda-enzymes.org/ ) affected PTDH-NAD + interaction and structural stability 13 . As a result, we found mutations acting on the NAD + binding site, such as the K76 mutants R237K and E266Q, while the others affect the structural stabilization and the activity of PTDH catalysis, or both.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

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+.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Virtual screening of retrieved compounds against VEGFR-2 was conducted using AutoDock Vina ( Abdelkader et al, 2022 ). Before commencing the docking studies, MGLTools 1.5.6 was used to convert the VEGFR-2 structure from its native format, pdb, to the docking-ready format, pdbqt by adding the polar hydrogen atoms and Gasteiger charges to the protein chain ( Baammi et al, 2022 ). Except for the exhaustiveness parameter, which was set to 100, all default values were retained.…”

Section: Methodsmentioning

confidence: 99%

Unleashing Nature’s potential: a computational approach to discovering novel VEGFR-2 inhibitors from African natural compound using virtual screening, ADMET analysis, molecular dynamics, and MMPBSA calculations

Baammi,

El Allali,

Daoud

2023

Front. Mol. Biosci.

Self Cite

View full text Add to dashboard Cite

One of the characteristic features of cancer is angiogenesis, the process by which new, aberrant blood vessels are formed from pre-existing blood vessels. The process of angiogenesis begins when VEGF binds to its receptor, the VEGF receptor (VEGFR). The formation of new blood vessels provides nutrients that can promote the growth of cancer cells. When it comes to new blood vessel formation, VEGFR2 is a critical player. Therefore, inhibiting VEGFR2 is an effective way to target angiogenesis in cancer treatment. The aim of our research was to find new VEGFR-2 inhibitors by performing a virtual screening of 13313 from African natural compounds using different in silico techniques. Using molecular docking calculations and ADMET properties, we identified four compounds that exhibited a binding affinity ranging from −11.0 kcal/mol to −11.5 Kcal/mol when bound to VEGFR-2. These four compounds were further analyzed with 100 ns simulations to determine their stability and binding energy using the MM-PBSA method. After comparing the compounds with Regorafenib, a drug approved for anti-angiogenesis treatment, it was found that all the candidates (EANPDB 252, NANPDB 4577, and NANPDB 4580), with the exception of EANPDB 76, could target VEGFR-2 similarly effectively to Regorafenib. Therefore, we recommend three of these agents for anti-angiogenesis treatment because they are likely to deactivate VEGFR-2 and thus inhibit angiogenesis. However, it should be noted that the safety and suitability of these agents for clinical use needs further investigation, as the computer-assisted study did not include in vitro or in vivo experiments.

show abstract

“…This approach effectively identifies the relationship between molecular structure and bioactivity and key factors regulating compound activity [15,16] . Molecular docking and dynamics are powerful approaches for understanding the structural interactions between binding molecules and protein targets, predicting the optimal binding form [17,18] . Furthermore, absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) analysis can be used to evaluate the bioavailability and toxicity profile of molecules [19,20] …”

Section: Introductionmentioning

confidence: 99%

“…[15,16] Molecular docking and dynamics are powerful approaches for understanding the structural interactions between binding molecules and protein targets, predicting the optimal binding form. [17,18] Furthermore, absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) analysis can be used to evaluate the bioavailability and toxicity profile of molecules. [19,20] In this present study, we employed Gaussian field-based 3D-QSAR and atom-based 3D-QSAR with the PHASE module (2021 version, Schrödinger, LLC, NY) to analyze a series of triazole derivatives with cytotoxic activities.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

View full text Add to dashboard Cite

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.

show abstract

Assessing the effect of a series of mutations on the dynamic behavior of phosphite dehydrogenase using molecular docking, molecular dynamics and quantum mechanics/molecular mechanics simulations

Cited by 9 publications

References 41 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

Unleashing Nature’s potential: a computational approach to discovering novel VEGFR-2 inhibitors from African natural compound using virtual screening, ADMET analysis, molecular dynamics, and MMPBSA calculations

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

Contact Info

Product

Resources

About