Discovery of novel VEGFR2-TK inhibitors by phthalimide pharmacophore based virtual screening, molecular docking, MD simulation and DFT

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

Keywords:

• Anticancer
• pharmacophore based virtual screening
• phthalimide derivatives
• molecular dynamics (MD) simulation
• VEGFR2-TK

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors are thankful to The Department of Science & Technology (SERB) File Number EEQ/2017/000197 and EMR/2017/004497, New Delhi, India for providing financial support and the authority of Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh, India, 495009, for providing the research facilities. One of the authors BWM (Ph.D. Registration no.195263503) thanks to DST-SERB Govt. of India, New Delhi (File No. EEQ/2017/000197) for the financial support in the form of fellowship and infrastructural support provided by host University.