Pyrazole-based inhibitors of B-Raf kinase

Biochemical scheme with interaction of wild-type BRAF proteins

N1-modified pyrazole

3D4Q

a novel pyrazole-based class of ATP competitive B-Raf inhibitors

H-bond interactions made by the oxime moiety were revealed in the X-ray structure of the B-Raf complex co-crystallized with inhibitor. SAR evaluation at the C4 position of the pyrazole ring was aimed toward retaining these contacts and simultaneously improving the poor aqueous stability at low pH that characterized the oxime series.

[(BRAF-BRAF)]+S.C.M.+S.C.M._____________________[(BRAF-S.C.M.)(BRAF-S.C.M.)]

[(BRAF-S.C.M.)]+[(BRAF-S.C.M.)]__________________[(BRAF-S.C.M.)(BRAF-S.C.M.)]

Biomarker development concept

_________________number condition _______max _____________min___________________error comput. SVD
(1)3d4q ______________5.12875_______________ _4.468e-19_______ 3.322e-24________________ __1.5019e-19
(2)3d4q(dimer)_ __21.7414 _______________ 1.568e-19_________2.8440e-41_________________9.081e-34

_____max RMSD__________First-Order Optimaly Measure
3.33874663756617e-13_________4.42060133588067e-07

3d4q(monomer)

(1)3d4q
(2 prot.+2 chem)

(2)3d4q(dimer)

If an optimized cost function for a specific PDB structure is not found, then we consider that this structure is formed incorrectly. Also for analysis structures we use the root maean squared deviation (RMSD).

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.

N1-modified pyrazole

B-Raf IC50 (nM)

0.03

IC50 values reflect the average from at least three separate experiments*.

B-Raf

B-Raf

B-Raf

pyrazole

pyrazole

B-Raf

B-Raf

the impossibility of finding a local minimum

*Данные вычисления амилоидных димеров здесь приведены для примера нормальных соотношений между колебательными модами, number condition and error SVD
Вычислительная ошибка 1.5019e-19 является слишком большой по сравнению с полученными значениями 3.322e-24

2.

3.

Table №2

Number

PDB

Explanation

Pyrazole-based inhibitors of B-Raf kinase

1.

3d4q

error computational SVD 1.5019e-19

Figure 1.Chemical three-dimensional structures of a small chemical molecule.

Figure 2.Three-dimensional structure of the BRAF protein monomer. The blue arrow indicates the graph of the search for the minimum of the function

3d4q

3d4q

Table №1

The results of the performed calculations for these three-dimensional structures do not allow at this stage to carry out further studies in order to determine the shift in thermodynamic equilibrium. Either comparison with a similar structure or direct agreement with experimental data is required.

Dependence of RMSD(root-mean-square deviation) on the configuration number.

Determination of the computational error of the SVD

*[Potent and selective pyrazole-based inhibitors of B-Raf kinase]