Design, synthesis, and biological evaluation of novel Bcr-AblT315I inhibitors incorporating amino acids as flexible linker

Facing the sudden outbreak of coronavirus disease 2019 (COVID‐19), it is extremely urgent to develop effective antiviral drugs against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Drug repurposing is a promising strategy for the treatment of COVID‐19. To identify the precise target protein of marketed medicines, we initiate a chemical biological program to identify precise target of potential antivirus drugs. In this study, two types of recombinant human coronavirus SARS‐CoV‐2 RdRp protein capturing probes with various photoaffinity labeling units were designed and synthesized based on the structure of FDA‐approved drugs stavudine, remdesivir, acyclovir, and aladenosine. Fortunately, it was found that one novel photoaffinity probe, RD‐1, could diaplayed good affinity with SARS‐CoV‐2 RdRp around the residue ARG_553. In addition, RD‐1 probe also exhibited potent inhibitory activity against 3CLpro protease. Taken together, our findings will elucidate the structural basis for the efficacy of marketed drugs, and explore a rapid and efficient strategy of drug repurposing based on the identification of new targets. Moreover, these results could also provide a scientific basis for the clinical application of marketed drugs.

Drug Development Research

Section: Resultsmentioning

confidence: 99%

Identification of potential targets against SARS‐CoV‐2 of antiviral drugs based on photoaffinity probes

Wang

Pan

et al. 2023

Self Cite

“…We have confirmed the structures of more than 300 compounds, and have compiled a database. The design concepts of the compounds, as well as the synthetic routes, have been reported in our previously published literature [21,22]. To identify compounds with a higher binding affinity than nilotinib, we used SP docking, resulting in the identification of 63 molecules.…”

Section: Methodsmentioning

confidence: 99%

“…In our previous research, our main focus was on the design and synthesis of inhibitors specifically targeting leukemia. Many compounds were derived from existing tyrosine kinase inhibitors, primarily nilotinib, incorporating molecular scaffolds, structural modifications, and optimization strategies [21,22]. Nilotinib primarily comprises an aromatic heterocyclic moiety containing a pyrimidine core, an aniline group substituted with trifluoromethyl and imidazole, and a linker that connects these two components (Figure 1B).…”

Section: Introductionmentioning

confidence: 99%

Identification of a Putative SARS-CoV-2 Main Protease Inhibitor through In Silico Screening of Self-Designed Molecular Library

Yang

et al. 2023

IJMS

Self Cite

There have been outbreaks of SARS-CoV-2 around the world for over three years, and its variants continue to evolve. This has become a major global health threat. The main protease (Mpro, also called 3CLpro) plays a key role in viral replication and proliferation, making it an attractive drug target. Here, we have identified a novel potential inhibitor of Mpro, by applying the virtual screening of hundreds of nilotinib-structure-like compounds that we designed and synthesized. The screened compounds were assessed using SP docking, XP docking, MM-GBSA analysis, IFD docking, MD simulation, ADME/T prediction, and then an enzymatic assay in vitro. We finally identified the compound V291 as a potential SARS-CoV-2 Mpro inhibitor, with a high docking affinity and enzyme inhibitory activity. Moreover, the docking results indicate that His41 is a favorable amino acid for pi-pi interactions, while Glu166 can participate in salt-bridge formation with the protonated primary or secondary amines in the screened molecules. Thus, the compounds reported here are capable of engaging the key amino acids His41 and Glu166 in ligand-receptor interactions. A pharmacophore analysis further validates this assertion.

“…Our previous research focused on designing and synthesizing inhibitors for leukemia [21][22] . Among these, Nilotinib is a second-generation inhibitor of the Bcr-Abl protein, a key kinase in chronic myeloid leukemia.…”

Section: Introductionmentioning

confidence: 99%

A Potential Molecular Inhibitor of the SARS-COV-2 Main Protease Obtained by Virtual Screening

Yang

et al. 2023

Preprint

Self Cite

SARS-CoV-2 has been out breaking around the world for more than three years and continues to evolve variants, which has become a major global health threat. Main protease (Mpro, also called 3CLpro) plays a key role in viral replication and proliferation, making it an attractive drug target. Here, we have identified novel potential inhibitor of Mpro by applying a virtual screening of hundreds Nilotinib structure-like compounds we designed and synthesized. The screened compounds were followed for the SP docking, XP docking, MM-GBSA analysis, IFD docking, MD simulation, ADME/T prediction and then enzymatic assay in vitro. We finally identified compound V291 as a potential SARS-COV-2 Mpro inhibitor with high docking affinity and enzyme inhibitory activity. Moreover, the docking results indicate that His41 is a favorable amino acid for pi-pi inter-actions, while Glu166 can participate in salt bridge formation with protonated primary or secondary amines in the screened molecules. Thus, compounds reported here are capable of engaging the key amino acids His41 and Glu166 in ligand-receptor interactions. Pharmacophore analysis further validates this assertion.