Molecular Docking for Natural Product Investigations: Pitfalls and Ways to Overcome Them

Abstract Natural products (NPs) are one of the key resources for ancient as well as modern remedies. Today, many scientists aim to discover the mechanisms of action behind the observed effects of plant-based medicines. Modern drug discovery till today profits from the advantageous properties of nature-derived compounds. However, NP-based activities are often challenging to define due to unspecific and multi-target effects. Molecular docking is often used as a computational and easily accessible method to propose a binding mode of NPs on a protein target. By revealing the interaction points between ligand and target, it enables one to determine the structural elements, responsible for a specific activity. Binding site and pharmacophore similarities are used to explain the multi-target effects of NPs. This knowledge allows us to simulate the effects of possible synthetic structural modifications to optimize desirable activities and to exclude undesired targets. Furthermore, docking can also be used to explore different targets to determine the most likely one for a ligand to bind, in virtual target fishing setups. In addition, this technique is often combined with other molecular modeling approaches, e.g., pharmacophore modeling or molecular dynamics simulations to predict activity and to explore binding mechanisms. Robust molecular docking studies, however, require a thorough analysis of the available data on the target and known binding modes. As the theoretical approach aims to calculate the direct interaction between a small molecule ligand and a protein target, it is vital that the experimental setup corresponds to this premise and does not measure a more general activity. In the current chapter, we want to present the methods and requirements for successful NP docking and to highlight state-of-the-art docking studies performed on NPs, which resulted in significant, and ideally experimentally validated, insights into their mechanism of action.