The Application Of Computaional Chemistry Methods In Natural Products Chemistry

This thesis focuses on some problems existing in natural products chemistry, which remains unsolved under current experimental conditions. We will provide some computational chemistry methods to solve these problems from three perspectives. Firstly, we determine absolute configurations for natural products through calculating compound derived electronic circular dichroism (ECD) spectra data. Secondly, virtual screening is used to identify the bioactive hits from natural products. Thirdly, we investigate the synthetic mechanism of the natural products in the bioprocess based on the frontier molecular orbits theory.It is difficult to determine the absolute configurations for natural products. Currently, only a few methods can be used, such as X ray single crystal diffraction, chemical derivatization. However, these methods are not applicable to complicated natural products, for it is hard to acquire crystal structures of these compounds which are also hard to be synthesized, while absolute configurations can be identified only through comparing computational spectra and experimental ones. Thus the method which just calculates the compound derived ECD spectra adopted in our work is more realizable and reliable. In particular, we calculate the ECD spectra of a sesquiterpene lactone and a sesquiterpene dimmer to determine the absolute configurations for them by comparing the computational results with the experimental ones respectively.As for virtual screening applications, we identify several natural products hits with potent inhibitory activities against matrix metalloproteinases (MMPs) and facipain-2(FP-2), respectively. Among them, a MMPs inhibitor shows superior inhibitory effect on the expression of MMP-2and active-MMP-9, as well as suppresses the wound-healing migration of MDA-MB-231cancer cells efficiently. Besides, a FP-2inhibitor exhibits potent antimalarial activity in the model of infected mice by intraperitoneal injection, and the highest reduction rate of the malaria parasites is64%. Moreover, according to the target images and the mass spectrometry data, we find that the compound could enter the cells of the malaria parasites in the trophozoite stage specifically. These results can help us know more about mechanisms of the natural products to interact with the target.Understanding the synthesis mechanism of the natural products is an important foundation for biosynthesis. We also provide a solution to elucidate certain biogenic synthesis mechanisms, which are difficult to be confirmed under current experimental conditions. Through analyzing the frontline orbits and transition states, we conclude that the dimerization reaction of the novel sesquiterpene dimer is a DA reaction, and the stereoselectivity of the reaction is caused by the steric hindrance, while the regioselectivity is caused by the hyperconjugation effects. These results refine the traditional DA reaction mechanism, and help us to understand the mechanism in a thorough way.