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Molecular Docking of Phytochemicals Targeting GFRs as Therapeutic Sites for Cancer: an In Silico Study.

ABSTRACT: Drug delivery in a safe manner is a major challenge in the drug development process. Growth factor receptors (GFRs) are known to have profound roles in the growth and progression of cancerous cells making these receptors a therapeutic target in the effective treatment of cancer. This work focused on exploring bioactive compounds that can target GFRs using in silico method. In this study, 50 bioactive compounds from different plant sources were screened as anticancer agent against GFRs using drug likeness parameters of Lipinski's rule of five. The molecular docking was performed between phytochemicals and GFRs. Ligands with acceptable drug likeness and binding energy comparable to the standard drugs were further screened to determine their pharmacokinetic activities. This study showed phytochemicals with the binding energy comparable with the standard drugs (Dovitinib and Gefitinib), while ADME, bioactivity score, and bioavailability radar analysis gave further insight on these compounds as potent anticancer agents.

SUBMITTER: Mendie LE

PROVIDER: S-EPMC8731131 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Molecular Docking of Phytochemicals Targeting GFRs as Therapeutic Sites for Cancer: an In Silico Study.

Mendie Love Edet LE Hemalatha S S

Applied biochemistry and biotechnology 20220106 1

Drug delivery in a safe manner is a major challenge in the drug development process. Growth factor receptors (GFRs) are known to have profound roles in the growth and progression of cancerous cells making these receptors a therapeutic target in the effective treatment of cancer. This work focused on exploring bioactive compounds that can target GFRs using in silico method. In this study, 50 bioactive compounds from different plant sources were screened as anticancer agent against GFRs using drug ...[more]

PMID: 34988844

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Project description:The dysregulation of the rat sarcoma (RAS) signaling pathway, particularly the MAPK/ERK cascade, is a hallmark of many cancers, leading to uncontrolled cellular proliferation and resistance to apoptosis-inducing treatments. Dysregulation of the MAPK/ERK pathway is common in various cancers including pancreatic, lung, and colon cancers, making it a critical target for therapeutic intervention. Natural compounds, especially phytochemicals, offer a promising avenue for developing new anticancer therapies due to their potential to interfere with these signaling pathways. This study investigates the potential of anticancer phytochemicals to inhibit the MAPK/ERK pathway through molecular docking and simulation techniques. A total of 26 phytochemicals were screened from an initial set of 340 phytochemicals which were retrieved from Dr. Duke's database using in silico methods for their binding affinity and stability. Molecular docking was performed to identify key interactions with ERK2, followed by molecular dynamics (MD) simulations to evaluate the stability of these interactions. The study identified several phytochemicals, including luteolin, hispidulin, and isorhamnetin with a binding score of -10.1±0 Kcal/mol, -9.86±0.15 Kcal/mol, -9.76±0.025 Kcal/mol, respectively as promising inhibitors of the ERK2 protein. These compounds demonstrated significant binding affinities and stable interactions with ERK2 in MD simulation studies up to 200ns, particularly at the active site. The radius of gyration analysis confirmed the stability of these phytochemical-protein complexes' compactness, indicating their potential to inhibit ERK activity. The stability and binding affinity of these compounds suggest that they can effectively inhibit ERK2 activity, potentially leading to more effective and less toxic cancer treatments. The findings underscore the therapeutic promise of these phytochemicals, which could serve as a basis for developing new cancer therapies.

Project description:Acute myeloid leukemia (AML) is one of the deadly cancers. Chemotherapy is the first-line treatment and the only curative intervention is stem cell transplantation which are intolerable for aged and comorbid patients. Therefore, finding complementary treatment is still an active research area. For this, empirical knowledge driven search for therapeutic agents have been carried out by long and arduous wet lab processes. Nonetheless, currently there is an accumulated bioinformatics data about natural products that enabled the use of efficient and cost effective in silico methods to find drug candidates. In this work, therefore, we set out to computationally investigate the phytochemicals from Brucea antidysentrica to identify therapeutic phytochemicals for AML. We performed in silico molecular docking of compounds against AML receptors IDH2, MCL1, FLT3 and BCL2. Phytochemicals were docked to AML receptors at the same site where small molecule drugs were bound and their binding affinities were examined. In addition, random compounds from PubChem were docked with AML targets and their docking score was compared with that of phytochemicals using statistical analysis. Then, non-covalent interactions between phytochemicals and receptors were identified and visualized using discovery studio and Protein-Ligand Interaction Profiler web tool (PLIP). From the statistical analysis, most of the phytochemicals exhibited significantly lower (p-value ≤ 0.05) binding energies compared with random compounds. Using cutoff binding energy of less than or equal to one standard deviation from the mean of the phytochemicals' binding energies for each receptor, 12 phytochemicals showed considerable binding affinity. Especially, hydnocarpin (-8.9 kcal/mol) and yadanzioside P (-9.4 kcal/mol) exhibited lower binding energy than approved drugs AMG176 (-8.6 kcal/mol) and gilteritinib (-9.1 kcal/mol) to receptors MCL1 and FLT3 respectively, indicating their potential to be lead molecules. In addition, most of the phytochemicals possessed acceptable drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Based on the binding affinities as exhibited by the molecular docking studies supported by the statistical analysis, 12 phytochemicals from Brucea antidysentrica (1,11-dimethoxycanthin-6-one, 1-methoxycanthin-6-one, 2-methoxycanthin-6-one, beta-carboline-1-propionic acid, bruceanol A, bruceanol D, bruceanol F, bruceantarin, bruceantin, canthin-6-one, hydnocarpin, and yadanzioside P) can be considered as candidate compounds to prevent and manage AML. However, the phytochemicals should be further studied using in vivo & in vitro experiments on AML models. Therefore, this study concludes that combination of empirical knowledge, in silico molecular docking and ADMET profiling is useful to find natural product-based drug candidates. This technique can be applied to other natural products with known empirical efficacy.

Dataset Information

Molecular Docking of Phytochemicals Targeting GFRs as Therapeutic Sites for Cancer: an In Silico Study.

Publications

Molecular Docking of Phytochemicals Targeting GFRs as Therapeutic Sites for Cancer: an In Silico Study.

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