In silico Enhancement of VEGFR-2 Binding Properties of 5- Amino-2-(3,4-Dimethoxyphenylsulfonamido)-5-Oxopentanoic Acid (SM-1) for Improving its Anticancer Activity

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S. MISHRA, K. SARKER, A. GHOSH, A. SAHA, S. SEN

Abstract

Previously, 5-Amino-2-(3,4-dimethoxyphenylsulfonamido)-5-oxopentanoic acid (SM-1) was established by the authors as a
potent antiangiogenic and anticancer agent in Multiple Myeloma with no toxic effect on normal cells. The primary
antiangiogenic activity and anticancer activity were checked using HUVEC and RPMI-8226 cell lines respectively. Further, the
antiangiogenic activity of SM-1 was confirmed, observing inhibition of phosphorylation at tyrosine 1175 residue of VEGFR-2,
with the help of western blot technique. It was also found to be non-toxic to normal epithelial cells, observing the cytotoxic
effect on VERO cell line. In the present investigation, SM-1 was taken as a lead molecule with an aim to design more
prospective drug candidates. It was modified by docking at the active site of VEGFR-2 using drug designing software, Discovery
Studio. Several grow points and scaffolds were strategically identified, and grow scaffold and scaffold hopping techniques were
applied. Out of 13,650 compounds generated by the software, 5 hit compounds were identified and selected based on the
docking results. The docking results were compared with SM-1 and sorafenib as reference compounds and it was observed that
the five-hit compounds have better interaction with the critical amino acid residues at the catalytic site of VEGFR-2 than SM-1.
The compounds may be synthesized and tested for antiangiogenic and anticancer activity in Multiple Myeloma in the future
investigations.

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