Insights Into The Resistance Mechanisms Of Topotecan And Antiviral Drugs

The long-term medication of many drugs often leads ultimately to their becomingdrug resistant and even ineffective in clinical applications. Based on the cause of itsoccurrence, drug resistance could be divided into two subtypes: intrinsic resistance andacquired resistance. While mutations on the target of a drug is the main cause ofacquired resistance. Therefore, understanding the impact of mutations on the structureof protein-drug complex and the interactions between drug and protein provides avaluable clue for revealing the molecular mechanism of drug resistance and designingimproved drugs to combat resistance.In this article, we first employed a series of computational approaches frommolecular dynamics (MD) simulations to steered molecular dynamics (SMD)simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA)binding free energy calculations to uncover the molecular principle of the topotecanresistance induced by three important mutations in DNA topoisomerase I, includingE418K, G503S and D533G. Our results demonstrate a remarkable correlation betweenthe binding free energies predicted by MM/GBSA and the rupture forces computed bySMD, and moreover, the theoretical results given by MM/GBSA and SMD are inexcellent agreement with the experimental data. In order to explore the drug resistancemechanism that underlies the loss of the binding affinity of topotecan,the binding modesof topotecan bound to the WT and mutated receptors were presented. The resultsillustrate that the mutations of E418K, G503S and D533G have great influence on thebinding of topotecan to topoisomerase I bound with DNA, and the variations of thepolar interactions play critical roles in the development of drug resistance.In addition, the resistance mechanisms of oseltamivir (OTV), zanamivir (ZNV), and peramivir (PRV) against the E119G mutant of2009A/H1N1neuraminidase werealso investigated. The predicted binding free energies from MM/GBSA indicate that theE119G mutation in NA confers resistance to all of the three studied inhibitors. Theordering of the level of drug resistance predicted by the binding free energies for thethree inhibitors is ZNV> PRV> OTV, which agrees well with the experimental data.Drug resistance arises primarily from the unfavorable shifts of the polar interactionsbetween NA and the inhibitors. It comes as a surprise that the mutation of Glu119thatcan form strong H-bonds with the inhibitors in the wild-type protein does not havedirect impact on the binding affinities of both OTV and PRV due to the regulation of thestrong unfavorable polar desolvation energies. The indirectly conformational variationsof the inhibitors, which caused by the E119G mutation, are responsible for the loss ofthe binding free energies. However, for ZNV, the E119G mutation has both direct andindirect influences on the drug binding.