Molecular dynamics simulations reveal a strong binding capacity of colossolactone H to the EGFR inactive conformation

The major side effects of in-use drugs, such as gefitinib, erlotinib and osimetinib, have led to inherent limitations and considerable concerns regarding the use of tyrosine kinase inhibitors (TKIs) in cancer treatment. Natural compounds can effectively inhibit the expression of epidermal growth factor receptor (EGFR) tyrosine kinase protein; therefore, they are considered not only a functional product but also a substitute in cancer therapy. Based on the experimental findings of the bioactivities of natural compounds extracted from <i>Ganoderma lucidum</i> belonging to the family <i>Ganodermataceae</i>, which are commonly known as <i>lingzhi</i> and have been used since ancient times in Asian traditional medicine, we performed a theoretical study on the anti-tumor abilities of these colossolactone derivatives. Our work aims to understand the molecular interactions between a lactone compound and an EGFR intracellular protein, a common target in the development of TKI cancer drugs. A series of 16 colossolactone derivatives were placed in either the ATP-competition region or the allosteric active and inactive sites to explore their binding mechanism and rank their binding affinities. The latter was determined using steered molecular dynamics simulations and the umbrella sampling method. Of the 16 natural derivatives, colossolactone <i>H</i> was found to bind strongly to the allosteric pocket of EGFR-TKI and did not compete with the first-generation TKIs, which prefer to interact with the ATP region of the EGFR active state. The binding affinity of this lactone was 16 kcal mol^-1. Our calculated results offer a rational explanation for previous experimental (<i>in vivo</i>) tests and promote the use of colossolactone H as a natural compound, providing an efficient synergistic drug combination for various cancer treatments.