Molecular dynamics-based insight of VEGFR-2 kinase domain: a combined study of pharmacophore modeling and molecular docking and dynamics

Parves, Md. Rimon; Riza, Yasir Mohamed; Alam, Sanjida; Jaman, Sadia

doi:10.1007/s00894-022-05427-x

Cited by 5 publications

(2 citation statements)

References 52 publications

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“…Therefore, these complexes are more stable than the complexes generated by Foretinib (−9 kcal/mol) and compound 22 (−8.8 kcal/mol) in the data set, suggesting that these compounds have a higher inhibitory potential against VEGFR-2. Furthermore, the three-dimensional binding interaction of the compounds (T1-T6) showed a similar H-binding interaction profile with Asp1046 and hydrophobic and electrostatic interactions with Val899, Val848, Ala866, Leu1035, Leu889, Leu1019, Leu1035, and Leu840, with compound 22, and Foretinib suggesting that these amino acids play a critical role in enhancing activity as reported in previous studies (Yousef et al, 2022;Parves et al, 2023). These compounds interact with a higher number of residues via hydrophobic interactions than molecule 22 and Foretinib, which increases their stability and affinity in the binding pocket of VEGFR-2.…”

Section: Docking Resultssupporting

confidence: 78%

Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives

Baammi,

El Allali,

Daoud

2023

Front. Mol. Biosci.

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More people are being diagnosed with resistant breast cancer, increasing the urgency of developing new effective treatments. Several lines of evidence suggest that blocking the kinase activity of VEGFR-2 reduces angiogenesis and slows tumor growth. In this study, we developed novel VEGFR-2 inhibitors based on the triazolopyrazine template by using comparative molecular field analysis (CoMFA) and molecular similarity indices (CoMSIA) models for 3D-QSAR analysis of 23 triazolopyrazine-based compounds against breast cancer cell lines (MCF -7). Both CoMFA (Q2 = 0.575; R2 = 0.936, Rpred2 = 0.956) and CoMSIA/SE (Q2 = 0.575; R2 = 0.936, Rpred2 = 0.847) results demonstrate the robustness and stability of the constructed model. Six novel compounds with potent inhibitory activity were carefully designed, and screening of ADMET properties revealed their good oral bioavailability and ability to diffuse through various biological barriers. When compared with the most active molecule in the data set and with Foretinib (breast cancer drug), molecular docking revealed that the six designed compounds had strengthened affinity (−8.9 to −10 kcal/mol) to VEGFR-2. Molecular Dynamics Simulations and MMPBSA calculations were applied to the selected compound T01 with the highest predicted inhibitory activity, confirming its stability in the active pocket of VEGFR-2 over 100 ns. The present results provided the basis for the chemical synthesis of new compounds with improved inhibitory properties against the breast cancer cell line (MCF -7).

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Section: Docking Resultssupporting

confidence: 78%

Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives

Baammi,

El Allali,

Daoud

2023

Front. Mol. Biosci.

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“…Drug design techniques, such as molecular docking and molecular dynamic simulations, have been used to study DNA binding and stability in solvents ( Ali et al, 2023c ). The new most dynamic scoring, particularly with molecular mechanics/Poisson−Boltzmann surface area (MM/PBSA) and QM/MM (quantum mechanics/molecular mechanics), has reduced false positives in virtual screening ( Parves et al, 2023 ). MM/GBSA-based drugs show promising activity, often superior to experimental therapies, leading to cost-effective and efficient high-throughput inhibitor screening ( Tabti et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

In silico and in vitro study of bioactive compounds of Nigella sativa for targeting neuropilins in breast cancer

Zafar,

Safder,

Imran Afridi

et al. 2023

Front. Chem.

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Introduction: Breast cancer poses a significant global challenge, prompting researchers to explore novel approaches for potential treatments.Material and Methods: For in vitro study we used thin layer chromatography (TAC) for phytochemical screening, total antioxidant capacity (TLC) assay for antioxidant capacity, and hemolytic activity test for toxicity of Neuropilins (NRPs). We performed bioinformatic analyses to predict protein structures, molecular docking, pharmacophore modeling, and virtual screening to reveal interactions with oncogenes. We conducted 200 ns Molecular Dynamics (MD) simulations and MMGBSA calculations to assess the complex dynamics and stability.Results: We identified phytochemical constituents in Nigella sativa leaves, including tannins, saponins, steroids, and cardiac glycosides, while phlobatannins and terpenoids were absent. The leaves contained 9.4% ± 0.04% alkaloids and 1.9% ± 0.05% saponins. Methanol extract exhibited the highest yield and antioxidant capacity, with Total Flavonoid Content at 127.51 ± 0.76 mg/100 g and Total Phenolic Content at 134.39 ± 0.589 mg GAE/100 g. Hemolysis testing showed varying degrees of hemolysis for different extracts. In-silico analysis indicated stable Neuropilin complexes with key signaling pathways relevant for anti-cancer therapy. Molecular docking scores at different possesses (0, C-50, C −80, C-120,C −150, C −200 ns) revealed strong hydrogen bonding in the complexes and showed −12.9, −11.6, and −11.2 binding Affinities (kcal/mol) to support their stability. Our MD simulations analysis at 200ns confirmed the stability of Neuropilin complexes with the signaling pathways protein PI3K. The calculated binding free energies using MMGBSA provided valuable quantitative information on ligand potency on different time steps. These findings highlight the potential health benefits of N. sativa leaves and their possible role in anti-cancer treatments targeting angiogenesis.Conclusion:Nigella sativa leaves have shown significant medical potential due to their bioactive compounds, which exhibit strong properties in supporting organogenic processes related to cancer. Furthermore, studies have highlighted the promising role of neuropilins in anticancer treatment, demonstrating stable interactions and potential as targeted therapy specifically for breast cancer.

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Computer‐Aided Design of VEGFR‐2 Inhibitors as Anticancer Agents: A Review

Uba

2024

J of Molecular Recognition

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Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR‐2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR‐2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well‐tolerated sunitinib and sorafenib, have been approved as VEGFR‐2 inhibitors. However, the widespread side effects linked to these VEGFR‐2 inhibitors—hypertension, epistaxis, proteinuria, and upper respiratory infection—motivate researchers to search for new VEGFR‐2 inhibitors with better pharmacokinetic profiles. The key molecular interactions required for the interaction of the small molecules with the protein target to produce the desired pharmacological effects are identified using computer‐aided drug design (CADD) methods such as pharmacophore and QSAR modeling, structure‐based virtual screening, molecular docking, molecular dynamics (MD) simulation coupled with MM/PB(GB)SA, and other computational strategies. This review discusses the applications of these methods for VEGFR‐2 inhibitor design. Future VEGFR‐2 inhibitor designs may be influenced by this review, which focuses on the current trends of using multiple screening layers to design better inhibitors.

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Molecular dynamics-based insight of VEGFR-2 kinase domain: a combined study of pharmacophore modeling and molecular docking and dynamics

Cited by 5 publications

References 52 publications

Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives

Potent VEGFR-2 inhibitors for resistant breast cancer: a comprehensive 3D-QSAR, ADMET, molecular docking and MMPBSA calculation on triazolopyrazine derivatives

In silico and in vitro study of bioactive compounds of Nigella sativa for targeting neuropilins in breast cancer

Computer‐Aided Design of VEGFR‐2 Inhibitors as Anticancer Agents: A Review

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