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Discovery of novel VEGFR2-TK inhibitors by phthalimide pharmacophore based virtual screening, molecular docking, MD
Balaji Wamanrao Matore1, Partha Pratim Roy1, Jagadish Singh1
1Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, Chhattisgarh, India.
Abstract:
Currently, numerous potent chemotherapeutic agents are available in the market but most of them show poor pharmacokinetics, lethal effects and drug resistance during their enduring use. The increased cancer cases, deaths and need of better treatment stimulates us to give newer lifesaving anticancer drugs. The phthalimide derivatives are structurally diverse and exert potential anticancer activity. In this regard, the 3D QSAR Pharmacophore model was developed and validated using fifty-eight phthalimide derivatives. The validation parameters corroborated the reliability and statistical robustness of CEASER Hypo 1. Three databases-NCI Open, Drug Bank, and Asinex were submitted to ADMET and drug-like filtering; 117893 drug-like compounds were mapped on CEASER Hypo 1; and 362 hits with IC50 <1 µM were discovered. These hits were docked on VEGFR2-TK, and in the form of results fifteen hits exhibited greater affinity than sorafenib. The top lead ASN 03206926 was subjected for MD simulation (100 ns) and RMSD, Rg, RMSF, number of hydrogen bonds, and SASA verified that the complex was stable, rigid and highly compact. Results demonstrated GLU885, PHE918, CYS919, LYS920, HIS1026, CYS1045, ASP1046 are the essential residues for favourable interactions. The binding free energy calculations support the affinity and stability revealed by docking and MD simulation. The DFT calculations, negative binding energy and lower HOMO-LUMO band gap revealed that the process is spontaneous and ASN 03206926 is very reactive. Following extensive analysis we suggest that the ASN 03206926 might be employed as a new VEGFR2-TK inhibitor for the treatment of breast and VEGFR2-TK associated cancers.Communicated by Ramaswamy H. Sarma.
Insights
Researchers developed a new anticancer drug candidate, ASN 03206926, from phthalimide derivatives. This potential VEGFR2-TK inhibitor shows promise for treating breast and VEGFR2-TK associated cancers.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Pharmacology
Background:
- Existing chemotherapeutics face challenges like poor pharmacokinetics, toxicity, and drug resistance.
- There is a critical need for novel anticancer agents to address rising cancer incidence and mortality.
Purpose of the Study:
- To design and identify novel phthalimide derivatives as potential anticancer agents.
- To develop a validated 3D QSAR pharmacophore model for phthalimide derivatives.
- To discover and validate new inhibitors targeting Vascular Endothelial Growth Factor Receptor 2 Tyrosine Kinase (VEGFR2-TK).
Main Methods:
- Development and validation of a 3D QSAR pharmacophore model (CEASER Hypo 1) using 58 phthalimide derivatives.
- Virtual screening of large compound databases (NCI Open, Drug Bank, Asinex) against the pharmacophore model.
- Molecular docking studies against VEGFR2-TK, followed by molecular dynamics (MD) simulation and binding free energy calculations for top hits.
- Density Functional Theory (DFT) calculations to assess reactivity and spontaneity.
Main Results:
- A robust pharmacophore model (CEASER Hypo 1) was established.
- Virtual screening identified 362 potential hits, with 15 showing higher affinity for VEGFR2-TK than sorafenib.
- The lead compound, ASN 03206926, demonstrated stable complex formation with VEGFR2-TK via MD simulations.
- Key amino acid residues (GLU885, PHE918, CYS919, LYS920, HIS1026, CYS1045, ASP1046) were identified as crucial for binding.
- DFT calculations indicated that ASN 03206926 is reactive and the binding process is spontaneous.
Conclusions:
- ASN 03206926 is a promising novel inhibitor of VEGFR2-TK.
- This compound has potential for the treatment of breast cancer and other VEGFR2-TK associated malignancies.
- The study highlights the utility of integrated computational approaches in drug discovery.
