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Pharmacophore-based virtual screening approaches to identify novel molecular candidates against EGFR through comprehensive computational approaches and in-vitro studies

Affiliation
Department of Biological Science, Faculty of Sciences, King Abdulaziz University ,Jeddah ,Saudi Arabia
Opo, F A Dain Md;
Affiliation
Embryonic Stem Cell Research Unit, King Fahd Medical Research Center, King Abdulaziz University ,Jeddah ,Saudi Arabia
Moulay, Mohammed;
Affiliation
Department of Biological Science, Faculty of Sciences, King Abdulaziz University ,Jeddah ,Saudi Arabia
Zari, Ali;
Affiliation
Department of Biological Science, Faculty of Sciences, King Abdulaziz University ,Jeddah ,Saudi Arabia
Alqaderi, Afnan;
Affiliation
Department of Biological Science, Faculty of Sciences, King Abdulaziz University ,Jeddah ,Saudi Arabia
Alkarim, Saleh;
Affiliation
Department of Biological Science, Faculty of Sciences, King Abdulaziz University ,Jeddah ,Saudi Arabia
Zari, Talal;
Affiliation
Department of Pharmacy, University of Asia Pacific ,Dhaka ,Bangladesh
Bhuiyan, Mohiuddin Ahmed;
Affiliation
King Fahd Medical Research Center, King Abdulaziz University ,Jeddah ,Saudi Arabia
Mahmoud, Maged Mostafa;
Affiliation
Department of Biological Science, Faculty of Sciences, King Abdulaziz University ,Jeddah ,Saudi Arabia
Aljoud, Fadwa;
Affiliation
King Fahd Medical Research Center, King Abdulaziz University ,Jeddah ,Saudi Arabia
Suhail, Mohd;
Affiliation
Department of Biological Science, Faculty of Sciences, King Abdulaziz University ,Jeddah ,Saudi Arabia
Edris, Sherif;
Affiliation
Embryonic and Cancer Stem Cell Research Group, King Fahd Medical Research Center, King Abdulaziz University ,Jeddah ,Saudi Arabia
Ramadan, Wafaa S.;
Affiliation
King Fahd Medical Research Center, King Abdulaziz University ,Jeddah ,Saudi Arabia
Kamal, Mohammad Amjad;
Affiliation
Department of Biology, Abdelhamid ibn Badis University ,Mostaganem ,Algeria
Nemmiche, Saïd;
Affiliation
Department of Biological Science, Faculty of Sciences, King Abdulaziz University ,Jeddah ,Saudi Arabia
Ahammad, Foysal

Alterations to the EGFR (epidermal growth factor receptor) gene, which primarily occur in the axon 18–21 position, have been linked to a variety of cancers, including ovarian, breast, colon, and lung cancer. The use of TK inhibitors (gefitinib, erlotinib, lapatinib, and afatinib) and monoclonal antibodies (cetuximab, panitumumab, and matuzumab) in the treatment of advanced-stage cancer is very common. These drugs are becoming less effective in EGFR targeted cancer treatment and developing resistance to cancer cell eradication, which sometimes necessitates stopping treatment due to the side effects. One in silico study has been conducted to identify EGFR antagonists using other compounds, databases without providing the toxicity profile, comparative analyses, or morphological cell death pattern. The goal of our study was to identify potential lead compounds, and we identified seven compounds based on the docking score and four compounds that were chosen for our study, utilizing toxicity analysis. Molecular docking, virtual screening, dynamic simulation, and in-vitro screening indicated that these compounds’ effects were superior to those of already marketed medication (gefitinib). The four compounds obtained, ZINC96937394, ZINC14611940, ZINC103239230, and ZINC96933670, demonstrated improved binding affinity (−9.9 kcal/mol, −9.6 kcal/mol, −9.5 kcal/mol, and −9.2 kcal/mol, respectively), interaction stability, and a lower toxicity profile. In silico toxicity analysis showed that our compounds have a lower toxicity profile and a higher LD 50 value. At the same time, a selected compound, i.e., ZINC103239230, was revealed to attach to a particular active site and bind more tightly to the protein, as well as show better in-vitro r esults when compared to our selected gefitinib medication. MTT assay, gene expression analysis (BAX, BCL-2, and β-catenin), apoptosis analysis, TEM, cell cycle assay, ELISA, and cell migration assays were conducted to perform the cell death analysis of lung cancer and breast cancer, compared to the marketed product. The MTT assay exhibited 80% cell death for 75 µM and 100µM; however, flow cytometry analysis with the IC 50 value demonstrated that the selected compound induced higher apoptosis in MCF-7 (30.8%) than in A549.

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License Holder: Copyright © 2022 Opo, Moulay, Zari, Alqaderi, Alkarim, Zari, Bhuiyan, Mahmoud, Aljoud, Suhail, Edris, Ramadan, Kamal, Nemmiche and Ahammad.

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