Structure-Based Drug Design and Virtual Screening. The FORECASTER (Suite2019-rev5679.1) developed by our group was used for the processing of chemical libraries and protein structures and for virtual screening. BIOVIA Discovery Studio (version v20.1.0.1929) by Dassault Systèmes was used to visualize the docking-based virtual screening results. PyMol (version 2.4.0a0) was used for additional structure visualization and generation of corresponding figures in this study. Library preparation. The ZINC molecular library with the following filters (1. Representation: 3D, 2. Reactivity: Hot, 3. Purchasability: Agent, 4. pH: Ref Mid, 5. Charge: 0, 5. Molecular Weight: 200 to 500, 6. LogP: -1 to 5.) was downloaded from the ZINC tranche browser (). This extracted library included more than 9 million compounds in 3D representation with hydrogen atoms added in sdf format. The acquired 3D Library was cleaned by the "Chemical library cleaning" module in FORECASTER. The full library was first processed by SMART (computing descriptors) and filtered by REDUCE to derive a focused library with desired physico-chemical properties and functional groups. In particular, only neutral molecules within molecular weights ranging from 150 to 550 g/mol and with at least one covalent warhead (aldehyde, boronic acid, ketone, Michael acceptor, nitrile, or epoxide) were included in this focused library. This finally led to the first library of 86,423 potential covalent inhibitors (library #1).