Cheminformatic profiling of Azardirachta indica phytochemicals as dual SHP2/HSP90 oncogenic inhibitors: Identification of nimbocinol, nimbidinin, and margolone.

Cancer therapy faces challenges due to drug resistance and signaling pathway redundancy, allowing cancer cells to evade treatment. Dual inhibition of Src homology region 2 domain-containing phosphatase-2 (SHP2) and heat shock protein 90 (HSP90) offers a promising strategy to overcome these limitations. We evaluated neem-derived compounds against SHP2 (PDB ID: 5EHR) and HSP90 (PDB ID: 1YET) using molecular docking, hierarchical clustering, and structural similarity analyses. Drug-likeness was assessed using Lipinski's rule of five, and Tanimoto similarity coefficients were calculated. Nimbocinol, nimbidin, and margolone showed promising binding affinities to both targets. Nimbocinol demonstrated superior binding to SHP2 (-10.463kcal/mol) compared to SHP099 (-10.009kcal/mol). Margolone formed specific interactions, including a salt bridge between its carboxylate group and His100 in HSP90. All compounds complied with Lipinski's rule, with margolone showing structural similarities to geldanamycin and SHP099. This study identifies neem-derived compounds as potential dual inhibitors of SHP2 and HSP90, presenting a paradigm shift in cancer therapeutic strategy. These findings provide a foundation for developing novel multi-targeted anticancer therapeutics.