Large library docking for novel SARS‐CoV‐2 main protease non‐covalent and covalent inhibitors

Abstract

Antiviral therapeutics to treat SARS‐CoV‐2 are needed to diminish the morbidity of the ongoing COVID‐19 pandemic. A well‐precedented drug target is the main viral protease (MPro), which is targeted by an approved drug and by several investigational drugs. Emerging viral resistance has made new inhibitor chemotypes more pressing. Adopting a structure‐based approach, we docked 1.2 billion non‐covalent lead‐like molecules and a new library of 6.5 million electrophiles against the enzyme structure. From these, 29 non‐covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 and 20 μM, respectively. Several series were optimized, resulting in low micromolar inhibitors. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. While the new chemotypes may aid further optimization of MPro inhibitors for SARS‐CoV‐2, the modest success rate also reveals weaknesses in our approach for challenging targets like MPro versus other targets where it has been more successful, and versus other structure‐based techniques against MPro itself.

Structure-Based Identification of Organoruthenium Compounds as Nanomolar Antagonists of Cannabinoid Receptors

“…Nevertheless, we must emphasize that we are not focusing on developing CB1 or CB2 antagonists but providing an SBDD strategy for exploring novel chemical space with metal complexes. Despite its known weaknesses, molecular docking is a practical technique for prioritizing potential binders from a large compound database for a specific target. − Although rare, molecular docking can also be used to identify potential targets from a protein structure database for a particular small molecular ligand. For example, the reverse docking approach has been proven to be powerful for drug repositioning, explaining molecular mechanisms, and detecting side effects. ,, Herein, we utilized reverse docking to identify the potential target of a rigid octahedral organoruthenium scaffold.…”

On the origins of SARS-CoV-2 main protease inhibitors

“…334 This comment is also likely valid for a number of aldehyde-bearing compounds which have been reported to be inhibitors of SARS-CoV-2 M pro . 91,196,335 In any case, a patent describes further structure-activity relationship studies around such pyridone derivatives which led to the modest SARS-CoV-2 M pro inhibitor 92. 336 In a 2013 patent, an array of inhibitors, such as the constrained azapeptide 93 featuring a rigidifying 2,6-dioxopiperidine component, 337 or macrocyclic-bearing peptides such as 94, 338 were claimed for their effects on 3CL proteases of picornaviruses, caliciviruses and coronaviruses.…”

“…15). 91 Starting from the less deconstructed ML188 (98), the analogues 108 and 109, 361 or the related MAT-POS-f2460aef-1 (110), 356 explored some other possibilities and the more elaborated pyrazine-bearing analogue 111 was also reported. 362 The design and synthesis of the analogue X77 (112) was never actually reported but this compound was cocrystallized with SARS-CoV-2 M pro in 2020 and the corresponding X-ray based structure (PDB 6W63) has been repeatedly used for virtual-based approaches.…”

“…80 Aside from these, quite a few virtual-based reports describe modest inhibition of SARS-CoV-2 M pro by not too obvious frequent hitters which could lead to original series of inhibitors. [81][82][83][84][85][86][87][88][89][90][91][92] However, as for the published results of high throughput or X-ray based screenings, 84,93 we chose to wait for some reports focusing on the actual hit to lead progression before including them in this text.…”

Electrochemical Formation of α-Ketoamides from Ketoximes through Non-Beckmann Mechanism Pathway

“…Indeed, roughly 25% of currently available pharmaceuticals and approximately two-thirds of prospective drug candidates contain at least one amide bond . In recent years, these structures have emerged as promising candidates for the development of drugs targeting the SARS-CoV-2 virus. − The presence of the α-ketoamide moiety within the structures of numerous valuable natural and synthetic molecules as evidence represents their key roles in the biological activities of these compounds. − α-Ketoamides have been also used in developing inhibitors of HIV protease, histone deacetylase (HDAC), cytokines, and epoxide hydrolase (Scheme A). − Furthermore, α-ketoamides stand as appealing candidates for synthetic chemists due to their facile conversion to various valuable functional groups through convenient traditional reaction conditions. Accordingly, in recent decades, there has been considerable focus on advancing traditional methods for constructing α-ketoamide motifs in synthetic organic chemistry .…”