Computational Exploration of Plant Natural Products Bioactivity and Bioavailability in Human Health

Natural products, par�cularly those derived from plants, are some of the most widely used small-molecule drugs today, with over half of all drugs approved in the past four decades naturally derived or closely related to natural products. This project uses computa�onal approaches to model nanoscale interac�ons between natural products from plants, fungi, or bacteria and their environment to facilitate use and effec�veness for natural products in human health and disease contexts. To this end, we have developed a molecular simula�on campaign to quan�fy the ligand-protein and ligand-membrane interac�ons fundamental to natural product u�liza�on and extrac�on. Since the natural product landscape is so broad, our focus is directed towards exis�ng compounds where we have exis�ng collabora�ons. For lignin, a polyaroma�c polymer found in plant cell walls, we are measuring binding to human hormone receptors to evaluate its poten�al as a replacement plas�cizer in industrial applica�ons. Cisprenyltransferase and the long polyisoprenoid chains it synthesizes offer a unique look at how natural product synthesis is controlled, even if the ligand does not fit inside the protein ac�ve site. Similarly, iden�fying a mitochondrial target for sorgoleone, a compound excreted in large quan��es by sorghum roots, would open new avenues to probe and alter metabolism in mitochondria. Other calcula�ons explore the membrane permeability of specific natural products used to treat cancer, such as vinblas�ne or taxol, across mul�ple membrane composi�ons to elucidate if membrane permeability changes between cell types drive differen�al efficacy of cancer treatments. A further systema�c treatment of membrane permeability in mul�component membrane models could pave the way for connec�ng modern lipidomics and transport kine�cs for small molecules. The simula�ons involved in this research use advanced sampling techniques like Hamiltonian replica exchange umbrella sampling (REUS), or free energy perturba�on (FEP) already used extensively in the PI laboratory to measure quan��es such as binding affini�es, free energy profiles across biological membranes, and other measures cri�cal to the biophysics of natural products in vivo.