Identification of novel chemical scaffolds against kinase domain of cancer causing human epidermal growth factor receptor 2: a systemic chemoinformatic approach

The Human epidermal growth factor receptor 2 (HER2) is expressed in high magnitude in several cancers. Designing new drug molecules that target kinase domain of the HER2 enzyme might provide an appealing platform. Considering this, herein, a multi-phase bioinformatic approach is applied to screen diverse natural and chemical scaffolds to identify compounds that fit best at the kinase domain of HER2. By doing so, three compounds; LAS_51187157, LAC_51217113, LAC_51390233 were pointed with docking score of -11.4 kcal/mol, -11.3 kcal/mol and -11.2 kcal/mol, respectively. In molecular dynamic simulation, the complexes behaved in a stable dynamic with no major local/global structural variations. The intermolecular binding free energies were further estimated that concluded LAC_51390233 complex was the most stable and has less entropy energy. The good docked affinity of LAC_51390233 with HER2 was confirmed by WaterSwap absolute binding free energy. The entropy energy demonstrated that LAC_51390233 has less freedom energy compared to others. Similarly, all three compounds revealed very favorable druglike properties and pharmacokinetics. All the selected three compounds were also non-carcinogenic, non-immunotoxicity, non-mutagenicity, and non-cytotoxic. In a nutshell, the compounds are interesting scaffolds and might be subjected to extensive experimental testing to reveal their real biological potency.Communicated by Ramaswamy H. Sarma