A new paradigm for drug discovery in the treatment of complex diseases: drug discovery and optimization

In the past, the drug research and development has predominantly followed a "single target, single disease" model. However, clinical data show that single-target drugs are difficult to interfere with the complete disease network, are prone to develop drug resistance and low safety in clinical use. The proposal of multi-target drug therapy (also known as "cocktail therapy") provides a new approach for drug discovery, which can affect the disease and reduce adverse reactions by regulating multiple targets. Natural products are an important source for multi-target innovative drug development, and more than half of approved small molecule drugs are related to natural products. However, there are many challenges in the development process of natural products, such as active drug screening, target identification and preclinical dosage optimization. Therefore, how to develop multi-target drugs with good drug resistance from natural products has always been a challenge. This article summarizes the applications and shortcomings of related technologies such as natural product bioactivity screening, clarify the mode of action of the drug (direct/indirect target), and preclinical dose optimization. Moreover, in response to the challenges faced by natural products in the development process and the trend of interdisciplinary and multi-technology integration, and a multi-target drug development strategy of "active substances - drug action mode - drug optimization" is proposed to solve the key challenges in the development of natural products from multiple dimensions and levels.