Virtual screening for novel FGFR2 inhibitors: Exploring Gefitinib-like compounds as promising therapeutic candidates

Abstract

Gefitinib, an established anticancer medication targeting Epidermal Growth Factor Receptor (EGFR), has faced challenges due to tumor resistance and relapse over time. A notable factor in Gefitinib resistance is the elevated expression of FGFR2. Combining Gefitinib with an FGFR2 inhibitor has been proposed to counteract this resistance and prolong the efficacy of EGFR-targeted therapy.To identify potential FGFR2 inhibitors, our study adopted a virtual screening approach using the PubChem database and a KNIME Workflow to filter compounds for Lipinski Violations. These selected compounds underwent evaluation for their binding affinity to FGFR2, with the aid of the AutoQSAR module to predict bioactivity. For comparison, Derazantinib, a known FGFR2-targeting anticancer agent, was used as a benchmark. Moreover, bioisosteric replacements were conducted for the top two compounds to enhance ADMET profiles and binding affinity.Results indicated that the leading compounds exhibited notably improved binding affinities toward FGFR2, surpassing Derazantinib's performance. These compounds engaged in significant interactions with specific amino acids, such as ASP 644, LYS 157, ASN 157, and TYR 566, forging unique connections. Additionally, ADMET predictions highlighted favorable oral absorption rates exceeding 75% for all tested compounds, including Derazantinib. Also, the bioisosteres demonstrated enhanced binding affinity compared to the original structures.This study uncovers potential FGFR2 inhibitors with good binding affinities, shedding light on their interactions with the target protein. While promising, further in vivo and in vitro investigations are essential to validate the anticancer potential of these compounds.