COVID-19: In silico identification of potent α-ketoamide inhibitors targeting the main protease of the SARS-CoV-2

Abstract

The COVID-19 has been creating a global crisis, causing countless deaths and unbearable panic. Despite the progress made in the development of the vaccine, there is an urge need for the discovery of antivirals that may better work at different stages of SARS-CoV-2 reproduction. The main protease (M pro ) of the SARS-CoV-2 is a crucial therapeutic target due to its critical function in virus replication. The α-ketoamide derivatives represent an important class of inhibitors against the M pro of the SARS-CoV. While there is 99% sequence similarity between SARS-CoV and SARS-CoV-2 main proteases, anti-SARS-CoV compounds may have a huge demonstration's prospect of their effectiveness against the SARS-CoV-2. In this study, we applied various computational approaches to investigate the inhibition potency of novel designed α-ketoamide-based compounds. In this regard, a set of 21 α-ketoamides was employed to construct a QSAR model, using the genetic algorithm-multiple linear regression (GA-MLR), as well as a pharmacophore fit model. Based on the GA-MLR model, 713 new designed molecules were reduced to 150 promising hits, which were later subject to the established pharmacophore fit model. Among the 150 compounds, the best selected compounds (3 hits) with greater pharmacophore fit score were further studied via molecular docking, molecular dynamic simulations along with the Absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. Our approach revealed that the three hit compounds could serve as potential inhibitors against the SARS-CoV-2 M pro target.

Deciphering the binding mechanism of inhibitors of the SARS-CoV-2 main protease through multiple replica accelerated molecular dynamics simulations and free energy landscapes

“…Despite significant progress in the development of MPIs, the binding mechanism and kinetic information about most inhibitors of the M pro have not been completely elucidated. [33][34][35][36][37] Therefore, understanding the molecular mechanism and conformational changes of inhibitor-M pro binding at the atomic level is critical for the development of highly effective MPIs.…”

Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives

“…In Figure 15 b (crystal structure of SARS-CoV-2 M PRO in complex with compound 12 , PDB code 6Y2F ), the X-ray experiment confirms the formation of the covalent adduct ( Figure 14 ): the α-ketoamide group enhances the interaction in the S1′ cleft thanks to the H bonds with His 41 , Gly 143 , Ser 144 , and Cys 145 , the S1 site accommodates the glutamine surrogate γ-lactam ring, the key fragment amidopyridone interacts with Glu 166 via two H bonds, and the tert -butyl moiety is inserted into the S2 pocket. 14 , 58 , 59 …”

“…Analysis of the in silico data revealed that all three molecules interacted efficiently and stably with SARS-CoV-2 M PRO (similar to the reference compound 12 ) and also exhibited favorable pharmacokinetic and toxicological profiles. 59 …”

“…The application of various computational approaches (QSAR modeling, pharmacophore modeling, molecular docking, and molecular dynamics simulations) enabled the discovery of a novel series of α-ketoamide compounds such as derivatives 16 – 18 (Figure ). Analysis of the in silico data revealed that all three molecules interacted efficiently and stably with SARS-CoV-2 M PRO (similar to the reference compound 12 ) and also exhibited favorable pharmacokinetic and toxicological profiles …”

Structure-based design and synthesis of copper(ii) complexes as antivirus drug candidates targeting SARS CoV-2 and HIV

“…as potent inhibitors against SARS-CoV-2 virus. [16][17][18][19][20][21][22][23][24][25][26][27] In the current epidemiological context, various molecular docking methodologies are progressing in several directions to develop novel medicines against SARS-CoV-2 virus, and the nature of the interaction between the crystal structure of copper complexes with a main protease of SARS-CoV-2 would be worthwhile studying. This work describes the structurebased design and synthesis of two novel square-planar trans-N 2 O 2 Cu(II) complexes [Cu(L 1 ) 2 ] (1) and [Cu(L 2 ) 2 ] (2) of 2-((Z)-(4methoxyphenylimino)methyl)-4,6-dichlorophenol (L 1 H) and 2-((Z)-(2,4-dibromophenylimino)methyl)-4-bromophenol (L 2 H) as potential inhibitors against the main proteases of the SARS-CoV-2 and HIV viruses.…”