Drug Selection by affinity to the target protein,
taking into account oncological mutations.
The software package developed by our team makes it possible to determine the effects of dozens of mutations in the target protein on the affinity of drug binding.
Allows you to determine the causes of resistance, the greatest and least efficiency, depending on the modification.
Allows you to create databases of the effectiveness of existing drugs, depending on modifications / mutations in the molecules interacting with them.
Our method include:
-determining the causes of drug resistance to the target protein depending on the oncogenic mutation,
- Inhibitory potency and binding ability of small molecules,
- Inhibitor binding constants; the drug resistance provides important information for the development of more potent and selective drugs for use in resistant individuals.
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Biochemical Analysis Software

This section provides and describes in detail a numerical method for determining the effect of mutations on binding to small chemical molecules. The method we have developed makes it possible to numerically determine such a parameter as:
1. the stability of a complex molecular complex consisting of a protein and a small molecule.
2.changes in the stability parameter for various oncogenic mutations in proteins upon binding to small chemicals molecules
3. indicate the direction of the change in affinity and can serve as a good predictor,
since it will allow the selection of small chemical molecules that increase the affinity for the selected oncogenic mutations in proteins.
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The numerical calculation results can be applied in the following biochemical studies:

  • 1
    Inhibitory potency and binding ability of small molecules.
  • 2
    Inhibitor dissociation constants for the wt and mutant kinases.
  • 3
    Enzyme kinetic parameters.
  • 4
    Explanation of the enhanced drug sensitivity of different mutants.
  • 5
    Changing in the binding site caused by the mutation on the enzyme's binding affinity for TKIs.
  • 6
    Enzyme kinetic assays and IC50 determinations.
  • 7
    Inhibitor binding constants; the drug resistance provides important information for the development of more potent and selective drugs for use in resistant individuals.

Examples using small molecules are given below

The originality of this article is that the developed biophysical model makes it possible:

  • To determine the key amino acid residues in the protein complex, which correspond to the maximum values of the potential energy of electrostatic interaction.
  • To determine the effect of point mutations in peptides on the stability of the resulting biological complexes with protein. To qualitatively determine the range of variation of Kd during point mutations, when peptides bind to the active protein site.
  • Identifying the change in the physical parameters of binding upon modification of the polypeptide chain of the protein
  • Taking into account mutations in proteins, the effect of mutations on binding to small chemical molecules, as well as on binding to an antibody
  • Analyzing the joint binding of two small chemical molecules, thus allowing the resulting complex biological effect of the influences of two chemical molecules on protein binding by observing allosteric binding or competitive inhibition

The method can be used to obtain preliminary results for the following cases:

  • 1
    Identification of key amino acid residues
  • 2
  • 3
    Alanine scan
  • 4
    Amyloid peptides
  • 5

Why choose us?

Our software allows you to determine the direction of change in affinity, so you can significantly save on the following experimental methods:
  • ELISAs
  • Gel-shift assays
  • Aanalytical ultracentrifugation
  • Surface plasmon resonance
  • Spectroscopic assays
  • Affinity electrophoresis
  • Isothermal Calorimetry
The physically grounded mathematical approach developed in this article, in addition to work on molecular dynamics, will theoretically predict the passage of the biochemical reaction in the selected direction with the given amino acid sequences and identify the stability of different areas of protein complexes by analyzing the potential energy matrix of electrostatic interaction between different sites of the biological complex. In the future, it will allow us to solve fundamental and applied problems of medicine, for example, to develop new drugs and to study the processes occurring in the development of diseases, which are actual problems.
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 or the half maximal inhibitory concentration (IC50).
There are many ways to measure binding affinity and dissociation constants,
such as
- ELISAs gel-shift assays
- analytical ultracentrifugation
- surface plasmon resonance
- spectroscopic assays affinity
- electrophoresis isothermal calorimetry.

You can also measure binding affinity when modifying a molecule as a way to see how changing its binding properties relates to the pathway or process you are studying. Our developed software allows us to determine the direction of the change in affinity during the mutations of amino acid chains during interaction with small chemical molecules.

In this study, we will show how it is possible to determine the range of changes in the affinity of small chemical molecules only using information about the three-dimensional structure of such a complex.
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Startup pitch decks

Startup pitch decks of high lifescience innovations. Toolbox medical innovations
At the moment, it is necessary to conduct a biological experiment each time in order to determine how the effect of an oncogenic mutation on the affinity for a small molecule, it is necessary to experimentally investigate the cellular response and determine the concentration for the half-inhibition of the enzyme.

The goal of our project is to develop a method that allows one to determine the stability of a molecular complex using the local three-dimensional structures of interacting reagents, which in turn affects the affinity of the components, which is reflected in the cellular response.

Technical information

Numerical determination of the stability of the biocomplex taking into account mutations in the protein

The document below provides a mathematical background. Thus, to express the conformational mobility of a polyatomic molecule in the IR region, one can use a formula of the form (43). At the same time, for correct use, it should be understood that the greater value (43) in comparison with the rest of the values will indicate that not large vibrations of individual chain links of a polyatomic molecule should be understood so that not the basic vibrations of an individual links protein complex can lead to a shift in the rest of the chain links of the polyatomic molecule and, as a consequence, to the exit from the state of equilibrium and transition to the state of the entire molecule.
Modeling the impact of point mutations on the stability of proteins. EXAMPLE 1 BIOLOGICAL SOFT
Thanks to the use of the software developed by us, you can determine the affinity of the biological complex before carry out the biological experiment. Binomial Soft will allow you to determine the range of variation of the experimental values in biological research. The purpose of our software development is to determine the affinity of a biological complex, which is comparable to such experimental values as Kd (a specific type of equilibrium constant), IC50 (the half maximal inhibitory concentration ), ΔH, potential energy of interaction. Moreover, we want to share our method with other people how to use methods by other laboratories around the world, as this will significantly accelerate the development of drugs against other diseases.
Video instruction for using the software package
Our next example examines the effect of mutations in the heavy and light chains of Rituximab on binding to CD20. The figure shows a tetramer consisting of two CD20 transmembrane proteins and two FABs, heavy and light chains We will introduce five mutations in turn into the active binding site with CD20 and analyze the change in stability. The graph on the right presents the obtained numerical results on a logarithmic scale of the change in the value of lg (cond (W)). We have rotated the graph by 90 degrees for convenience of presentation, opposite each mutation the observed biological effect is shown, as well as the change in affinity in multiples.
Determination of antibody-antigen interaction using biological software

Additional information on small chemical molecules which are given as examples

A number of structures in the Protein Data Bank (PDB) contain adenosine 5′-(β,γ-imido)triphosphate (AMPPNP), a nonhydrolysable analog of ATP in which the bridging O atom between the two terminal phosphate groups is substituted by the imido function. Under mild conditions imides do not have acidic properties and thus the imide nitrogen should be protonated. However, an analysis of protein structures containing AMPPNP reveals that the imide group is deprotonated in certain complexes if the negative charges of the phosphate moieties in AMPPNP are in part neutralized by coordinating divalent metals or a guanidinium group of an arginine.
[Deprotonated imidodiphosphate in AMPPNP-­containing protein structures ]
Tumor cell turnover modulates the speed of selection against drug resistance by amplifying the effects of competition and resistance costs
Adenylylimidodiphosphate: effect of contaminants on adenylate cyclase activity
ATP analogue adenylyl-imidodiphosphate (AMP-PNP)
Gefitinib is an anilinoquinazoline with antineoplastic activity. Gefitinib inhibits the catalytic activity of numerous tyrosine kinases including the epidermal growth factor receptor (EGFR), which may result in inhibition of tyrosine kinase-dependent tumor growth. Specifically, this agent competes with the binding of ATP to the tyrosine kinase domain of EGFR, thereby inhibiting receptor autophosphorylation and resulting in inhibition of signal transduction. Patients with advanced epidermal growth factor receptor (EGFR) mutated non–small- cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and afatinib, show improved progression-free survival (PFS) compared with standard chemo- therapy as first-line therapy.
Cancer researchers are medical scientists research on carcinoma (cancer)
Gefitinib (Iressa®) is a selective small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR TKI) indicated for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR tyrosine kinase.
Gefitinib (Iressa) is an orally active TK inhibitor
(TKI) that blocks signal transduction pathways implicated
in cancers. The structures of the L858R and G719S mutants complexed with either AMPPNP or the inhibitors, gefitinib and AEE788, revealed that the overall conformation and ligand-binding modes are very similar to those of the wild-type EGFR-TK in the active
cancer treatment research medicine software
CH7233163 as having the potential to overcome EGFR-Del19/T790M/C797S. CH7233163 showed potent antitumor activities against tumor with EGFR-Del19/T790M/C797S in vitro and in vivo. In addition to EGFR-Del19/T790M/C797S, the characterization assays showed that CH7233163 more selectively inhibits various types of EGFR mutants (e.g., L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19, and L858R) over wild type.
cancer, oncology, medicine, research, software
Rociletinib (CO-1686) is an irreversible, mutant-selective EGFR inhibitor[52]. It is a medication developed to treat non-small cell lung carcinomas with a specific mutation. It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor. It was being developed by Clovis Oncology as a potential treatment for non-small-cell lung cancer [53]
Cancer. Medicine. software oncology research
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