Molecular modeling study of pyrrolidine derivatives as novel myeloid cell leukemia-1 inhibitors through combined 3D-QSAR, molecular docking, ADME/Tox and MD simulation techniques

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

doi:10.1080/07391102.2023.2183032

Cited by 11 publications

(2 citation statements)

References 66 publications

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“…To perform docking by re-docking the co-crystallized ligand at the Tubulin enzyme Fig. 4 represented the superimposed view of docked conformation 45 – 49 and the co-crystallized ligand and the RMSD value is 1.084 Å. The RMSD (Root Mean Square Distance) of the docked co-crystallized ligand was within the reliable range of 2 Å.…”

Section: Resultsmentioning

confidence: 99%

QSAR, ADMET, molecular docking, and dynamics studies of 1,2,4-triazine-3(2H)-one derivatives as tubulin inhibitors for breast cancer therapy

Moussaoui,

Baammi,

Soufi

et al. 2024

Sci Rep

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Breast cancer remains a leading cause of cancer-related deaths among women globally, necessitating the development of more effective therapeutic agents with minimal side effects. This study explores novel 1,2,4-triazine-3(2H)-one derivatives as potential inhibitors of Tubulin, a pivotal protein in cancer cell division, highlighting a targeted approach in cancer therapy. Using an integrated computational approach, we combined quantitative structure–activity relationship (QSAR) modeling, ADMET profiling, molecular docking, and molecular dynamics simulations to evaluate and predict the efficacy and stability of these compounds. Our QSAR models, developed through rigorous statistical analysis, revealed that descriptors such as absolute electronegativity and water solubility significantly influence inhibitory activity, achieving a predictive accuracy (R2) of 0.849. Molecular docking studies identified compounds with high binding affinities, particularly Pred28, which exhibited the best docking score of − 9.6 kcal/mol. Molecular dynamics simulations conducted over 100 ns provided further insights into the stability of these interactions. Pred28 demonstrated notable stability, with the lowest root mean square deviation (RMSD) of 0.29 nm and root mean square fluctuation (RMSF) values indicative of a tightly bound conformation to Tubulin. The novelty of this work lies in its methodological rigor and the integration of multiple advanced computational techniques to pinpoint compounds with promising therapeutic potential. Our findings advance the current understanding of Tubulin inhibitors and open avenues for the synthesis and experimental validation of these compounds, aiming to offer new solutions for breast cancer treatment.

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Section: Resultsmentioning

confidence: 99%

QSAR, ADMET, molecular docking, and dynamics studies of 1,2,4-triazine-3(2H)-one derivatives as tubulin inhibitors for breast cancer therapy

Moussaoui,

Baammi,

Soufi

et al. 2024

Sci Rep

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“…To address the missing residues, we employed “Build Structure” from Chimera’s modeling tools to rectify the protein structure. Prior to the docking analysis, we prepared the VEGFR-2 protein by removing water molecules, ions, and the ligand ( Tabti et al, 2023 ). The protonation of the amino acids was analyzed on the H++ server, and the hydrogen atoms were added to the whole structure.…”

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

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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.

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Discovery of novel indoleamine 2,3-dioxygenase-1 (IDO-1) inhibitors: pharmacophore-based 3D-QSAR, Gaussian field-based 3D-QSAR, docking, and binding free energy studies

et al. 2023

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Molecular modeling study of pyrrolidine derivatives as novel myeloid cell leukemia-1 inhibitors through combined 3D-QSAR, molecular docking, ADME/Tox and MD simulation techniques

Cited by 11 publications

References 66 publications

QSAR, ADMET, molecular docking, and dynamics studies of 1,2,4-triazine-3(2H)-one derivatives as tubulin inhibitors for breast cancer therapy

QSAR, ADMET, molecular docking, and dynamics studies of 1,2,4-triazine-3(2H)-one derivatives as tubulin inhibitors for breast cancer therapy

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

Discovery of novel indoleamine 2,3-dioxygenase-1 (IDO-1) inhibitors: pharmacophore-based 3D-QSAR, Gaussian field-based 3D-QSAR, docking, and binding free energy studies

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