Molecular Simulations in the Times of COVID-19 and Opioid Crisis




11:00 a.m.


Zoom (email for the link)


Jana Shen (Professor and Co-director of Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD)


The Shen group develops and applies molecular simulation and data science tools to advance the understanding of structure-function relationships of proteins and facilitate the design of novel therapeutics as well as functional materials. Recent tool development enables accurate assessment of reactive cysteine and lysine sites in proteins for targeted covalent inhibitor design [1]. Recent application studies examined the proton-coupled conformational dynamics of SARS-CoV-2 main protease [2] and fentanyl binding and unbinding at the mu-opioid receptor [3-4]. In the first part of the talk, I will discuss our recent progress in elucidating the structure-function relationships of the main protease and its (Omicron) mutants of the SARS-CoV-2 virus. The recently approved COVID-19 drug nirmatrelvir by Pfizer (trade name PAXLOVID) is a main protease inhibitor. Active surveillance of the continually emerging mutations is an important strategy for developing new inhibitors to combat drug resistance arising from natural evolution or drug treatment. In the second part of the talk, I will discuss our progress in understanding the binding and unbinding mechanisms as well as developing protocols to predict the residence times of fentanyl and morphine analogs at the muopioid receptor. Fentanyl overdose death has reached a new record level during the COVID-19 pandemic; however, the molecular mechanism of how fentanyl binds and activates its molecular target mu-opioid receptor remains poorly understood. X-ray crystal structure of fentanyl bound muopioid receptor is yet to be determined. Our work discovered a secondary binding mode; the developed protocols may be used to inform evaluation of strategies for opioid overdose reversal.


1. Liu R, Yue Z, Tsai CC, and Shen J*, Assessing lysine and cysteine reactivities for designing targeted covalent kinase inhibitors. J Am Chem Soc 141: 6553-6560 (2019).

2. Verma N, Henderson JA, and Shen J*, Proton-Coupled Conformational Activation of SARS Coronavirus Main Proteases and Opportunity for Designing Small-Molecule Broad-Spectrum Targeted Covalent Inhibitors. J Am Chem Soc 142: 21883–21890 (2020).

3. Vo Q, Mahinthichaichan P, Shen J*, Ellis CR*, How fentanyl recognizes mu-opioid receptor. Nat Commun 12: 984 (2021).

4. Mahinthichaichan P, Vo Q, Ellis CR, Shen J*, Kinetics and Mechanism of Fentanyl Dissociation from the μ-Opioid Receptor. JACS Au 1: 2208-2215 (2021).