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Organometallic inhibitor CNS292
Biochemical scheme with interaction of wild-type BRAF proteins
Organometallic inhibitor CNS292
A cocrystal structure of CS292 in complex with the BRAF kinase domain reveals that CS292 binds to the ATP binding pocket of the kinase and is an ATP competitive inhibitor. The structure of the kinase–inhibitor complex also demonstrates that CS292
binds to BRAF in an active conformation and suggests a mechanism for regulation of BRAF by phosphorylation and BRAFV600E oncogene-induced activation. The structure of CS292 bound to the active form of the BRAF kinase also provides a novel scaffold for the design of BRAFV600E oncogene
selective BRAF inhibitors for therapeutic application.


Taken together, structural evidence reveals extensive and specific interactions between CS292 and the ATP binding pocket of the BRAF kinase domain, establishing CS292 as an ATP competitive inhibitor and
confirming its potent inhibitory properties against both BRAFWT and BRAFV600E.
Dose–response curves of CS292 from an ELISA-based BRAF kinase inhibition assay
CS292 Concentrarion ( M x 10____ )
The most potent BRAF inhibitor, CS292, was also shown to have an 2-fold selectivity for BRAFV600E (IC50 = 0.21 мM) over the wild-type enzyme
Agreement between calculated and experimental data
Fig. Crystal Structure of Wild Type BRAF kinase domain in complex with organometallic inhibitor CNS292

Fig. Graph for determining the normality of the distribution for the subsequent determination of the change in information entropy.
number condition
max eigenvalue
min eigenvalue
error computational SVD
3q4c (wt)
Figure 3: Dependence of RMSD(root-mean-square deviation) on the configuration number
The fig.1 shows a rapidly oscillating character, which indicates the impossibility of finding a local minimum: optimization completed because at the initial point, the objective function is nondecreasing in feasible directions. As follows from the fig.1 the local minimum no found.
Dependence of RMSD(root-mean-square deviation) on the configuration number.

The structure of the PDB did not pass the check for the correctness of the construction

Below are the results of changing the affinity of the BRAF protein with a small chemical molecule.
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