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…

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.