6 Conclusions and Future Prospective
Recent advances in cryo-EM have enabled us to use single-particle cryo-EM as a
method of choice to resolve solution-state 3D structures of proteins and protein
complexes at atomic resolution, thus breaking the cryo-EM resolution barrier to
facilitate SBDD [6]. In recent years, many pharmaceutical companies like Bayer,
Merck Research Laboratories, Sonafi, AstraZeneca, Regeneron Pharmaceuticals,
NovAliX, Genentech etc. have realized the importance of this method and started
hiring experts in single-particle cryo-EM to get involved in their SBDD pipeline.
Table 1 lists the protein structures with bound ligands solved by single particle
cryo-EM at resolution 2.5 Å or better; i.e., five of the structures have bound
inhibitors/glycans, which underscore the importance of single-particle cryo-EM in
SBDD. Apart from these, there are many more structures with bound ligands in the
EMDB at resolutions below 2.5 Å. The future of this technique will be in obtaining
Fig. 7 Pharmacologically important target proteins (beige color) (modeled using the cryo-EM
electron potential 3D reconstruction map) in complex with inhibitor (shown as stick model). The
cryo-EM map of the inhibitors are shown as blue mesh. a 3.6 Å reconstruction of 20S
Plasmodium falciparum proteasome [114] with bound inhibitor Mor-WLW vinyl sulfone
(EMD3231) (PDB ID: 5fmg). b 2.9 Å cryo-EM reconstruction of complete 70S Escherichia coli
ribosome with bound antibiotic kirromycin [115] (EMD 2847, PDB ID: 5afi). c 2.3 Å resolution
3D reconstruction of anticancer drug target human p97 with bound allosteric inhibitor
UPCDC30245 [10]
394
R. Natesh
Recent advances in cryo-EM have enabled us to use single-particle cryo-EM as a
method of choice to resolve solution-state 3D structures of proteins and protein
complexes at atomic resolution, thus breaking the cryo-EM resolution barrier to
facilitate SBDD [6]. In recent years, many pharmaceutical companies like Bayer,
Merck Research Laboratories, Sonafi, AstraZeneca, Regeneron Pharmaceuticals,
NovAliX, Genentech etc. have realized the importance of this method and started
hiring experts in single-particle cryo-EM to get involved in their SBDD pipeline.
Table 1 lists the protein structures with bound ligands solved by single particle
cryo-EM at resolution 2.5 Å or better; i.e., five of the structures have bound
inhibitors/glycans, which underscore the importance of single-particle cryo-EM in
SBDD. Apart from these, there are many more structures with bound ligands in the
EMDB at resolutions below 2.5 Å. The future of this technique will be in obtaining
Fig. 7 Pharmacologically important target proteins (beige color) (modeled using the cryo-EM
electron potential 3D reconstruction map) in complex with inhibitor (shown as stick model). The
cryo-EM map of the inhibitors are shown as blue mesh. a 3.6 Å reconstruction of 20S
Plasmodium falciparum proteasome [114] with bound inhibitor Mor-WLW vinyl sulfone
(EMD3231) (PDB ID: 5fmg). b 2.9 Å cryo-EM reconstruction of complete 70S Escherichia coli
ribosome with bound antibiotic kirromycin [115] (EMD 2847, PDB ID: 5afi). c 2.3 Å resolution
3D reconstruction of anticancer drug target human p97 with bound allosteric inhibitor
UPCDC30245 [10]
394
R. Natesh