Computational chemistry has been applied in the area of computer aided drug design (CADD) to increase the pace of drug discovery, in a large part to guide synthetic teams toward promising targets. Where large libraries of data already exist, machine learning and data analysis methods may provide insights toward these targets; however, in the absence of large libraries of data, more physically rooted methods, such as Monte Carlo docking approaches or molecular dynamics (MD) simulations are more applicable. In contrast to CADD, where a given receptor is targeted by many ligands, our work focusses on targeting a given ligand with many abiotic receptors. In order to access the binding energies of these ligand-receptor complexes, MD approaches are used in order to generate reasonable bound conformations and to estimate their respective binding energies. Bound conformations are found by carrying out temperature replica exchange molecular dynamics (T-REMD) from the disassociated state of the receptor and ligand. Gaussian mixture modeling is used to cluster the bound conformations found and gives information about the distribution of these conformers. Following, adaptive steered molecular dynamics (ASMD) is used to estimate the binding energies of the bound ligand-receptor conformers. This technique takes advantage of the non-equilibrium Jarzynski equality which relates the irreversible work of many individual reaction paths to the difference in free energy between the two states. Specifically, the binding of fentanyl to a library of 20 receptors has been investigated in efforts toward the development of an antidote for fentanyl overdose. In medicine, this work could be applied to the creation of reversal agents for drugs with harmful side effects and antidotes for non-intentional exposures to toxicants. Taking inspiration from the field of CADD, the application of MD-based screening methods may guide the targeted synthesis of promising abiotic receptors for the sequestration of specific ligands.

Using replica exchange and steered molecular dynamics to probe the complexation geometries and binding affinities of fentanyl toward abiotic receptors: A blind challenge

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.