Molecular characterization of COVID-19 therapeutics: luteolin as an allosteric modulator of the spike protein of SARS-CoV-2

Abstract

The interactions between the receptor binding domain (RBD) of SARS-CoV-2 and the angiotensin-converting enzyme 2 (ACE2) are crucial for viral entry and subsequent replication. Given the large and featureless contact surfaces between both proteins, finding a suitable small-molecule drug that can bind and disrupt regulatory pathways has remained a challenge. A promising therapeutic alternative has been the use of small compounds that bind at the protein–protein interface or at distal “hotspots” and induce conformational changes that inhibit or stabilize protein–protein interactions (PPIs). In this work, we conduct large-scale all-atom explicit solvent simulations of the top scoring compounds from a recent large-scale high-throughput docking screening to investigate their interaction with the RBD domain of the spike (S) protein in complex with ACE2. We identify several promising candidates that exhibit a large negative free energy of binding to the RBD/ACE2 complex based on ab initio thermodynamic integration calculations. A systematic structural analysis of two glycosylation profiles of the RBD/ACE2 complex reveals the important role glycans play in modulating the binding of small-molecules. Cross correlation, fluctuation and strain analysis identify several of these compounds as effective PPI modulators that inhibit or stabilize the protein–protein interactions of RBD/ACE2 based on the glycosylation profile. Among them, luteolin, a drug currently approved for asthma, exhibits an intense allosteric effect when it binds to a previously unidentified distal binding site of the RBD domain far from the RBD and ACE2 interface which may serve as a potential target for future drug discovery.