Biochemical software.

Examples of calculated data obtained for Imatinib

The purpose of this work is to develop and test a new biophysical approach, which is implemented as a software package to determine changes in the direction of affinity changes for various amino acid residue substitutions in the protein when binding to various small chemical molecules.


Small molecule drugs accounted for 84% of the total pharmaceutical industry revenue in 2014. In 2015, a total of 45 new molecular entities were approved in the United States, out of which 33 were small molecules. The versatility of small molecule drugs (which can range from global blockbusters to targeted therapies to orphan drugs), and their ability to be formulated into pills and tablets are driving the demand for these drugs.
In 2015, the revenues of Contract Research Organizations (CROs) and CDMOs, focusing on the development of small molecules, increased by 15-20% .
On average, the cost of drug development ranges between USD 1.5-3 billion and has an average cost of around USD 2.6 billion. This high cost of drug development is a result of the high failure rate of experiments and relatively low-efficiency figures involved in the initial phases of drug discovery. Most of the small molecule drug discovery cost lies in the same bracket. Thus, developing such drugs always involves
high costs, which cannot be borne by new entrants or small-scale laboratories; this is limiting the market scope.
Therefore, developing a method to reduce the cost of preclinical studies on small molecules is particularly relevant at the present time.

Imatinib is used to treat certain types of leukemia (cancer that begins in the white blood cells) and other cancers and disorders of the blood cells. Imatinib is also used to treat certain types of gastrointestinal stromal tumors.
Imatinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells.
Imatinib also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF)/c-kit; the SCF/c-kit receptor tyrosine kinase is activated in gastrointestinal stromal tumor (GIST). This agent inhibits proliferation and induces apoptosis in cells that overexpress these oncoproteins.[2]
The results of applying our technique can be of good help for the pre-experimental determination of such quantities as the affinity expressed by the dissociation constant Kd or the half maximal inhibitory concentration (IC50).

Note that the results of numerical calculations, which are given in the article, can be applied in the following biochemical studies:

Inhibitory potency and binding ability of small molecules.
Inhibitor dissociation constants for the wt and mutant kinases.
Enzyme kinetic parameters.
Explanation of the enhanced drug sensitivity of different mutants.
Changing in the binding site caused by the mutation on the enzyme's binding affinity for TKIs.
Enzyme kinetic assays and IC50 determinations.
Inhibitor binding constants; the drug resistance provides important information for the development of more potent and selective drugs for use in resistant individuals.
Peroxisome proliferator-activated receptor (PPAR ) belongs to the thyroid hormone receptor-like nuclear receptor subfamily 1, which is one of the ligand-activated transcription factors. PPAR forms a heterodimer with retinoid X receptors (RXRs), recruits coactivators, and then binds to the cognate peroxisome proliferative response elements on target genes. PPAR is a good therapeutic target for type 2 diabetes mellitus, as well as other metabolic diseases including obesity and atherosclerosis.

This section compares experimental and numerical data on the effect of R288A substitution in PPAR on imatinib binding and analyzes the effect of R288A substitution on dimer complex affinity changes. Imatinib is a specific tyrosine kinase receptor inhibitor that is used in the therapy of Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumors, both of which are marked by an abnormal, constitutively expressed tyrosine kinase that causes unregulated cell growth. This section of the article will analyze the substitution of R288A in PPAR° when binding with imatinib.
Fig. 1 shows the three-dimensional structure of such a PPAR°-imatinib complex. The following graph b)-c) shows the combined experimental and calculated graphs for the replacement of R288A in the Human PPARgamma protein when it binds to imatinib and the effect of this replacement on the affinity of the dimer complex. Experimental
data are shown in red and calculated data are shown in blue.
As stated earlier, the direction of changes in affinity for the calculated and experimental plots in our studies are directional. Thus, a decrease in Kd and lg(cond(W)) values, when R288A is replaced with PPAR°, leads to an increase in the affinity of the PPAR°-imatinib dimer complex

Chemical structure of Imatinib

In the process of obtaining the calculated parameters, we use the method of quantum mechanical calculations. We get the distribution of charges, as well as calculate the conformational mobility of a small chemical molecule.
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Calculation of additional physical parameters of the small chemical molecule Imatinib
Direction of affinity change
A value lg(cond(W)) that shows the stability of a biological complex and shows the direction of change in the affinity of a dimer under various mutations.

Chemical structure of Imatinib-PPAR dimer with indication of key amino acid residues

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The structure of imatinib-bound PPAR° R288A mutant, indicating the key amino acid residues. PDB 6KTN a), results of experimental a) and numerical b) measurements of affinity changes upon R288A substitution in PPARgamma upon binding to imatinib. Surface plasmon resonance (SPR) analyses of the binding affinities for imatinib of PPAR° WT in the ligand-binding domain and PPAR° R288A mutant in the ligand-binding domain b) and dependence of lg(cond(W)) value on amino acid residue replacement of R288A binding with imatinib c)

Thus, our developed numerical method makes it possible to determine the range of stability changes of dimeric complexes involving a small chemical molecule and a protein molecule in the presence of a three-dimensional structure of the dimeric complex. Applying our method will make it possible to identify mutations that lead to the decreased/increased affinity of components.

Examples using small molecules are given below

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