Examples of calculated data obtained for Erlotinib
Biochemical software.
Medicinal Chemistry.

Erlotinib

Erlotinib is used to treat certain types of non-small cell lung cancer that has spread to nearby tissues or to other parts of the body in patients who have already been treated with at least one other chemotherapy medication and have not gotten better. Erlotinib is also used in combination with another medication (gemcitabine [Gemzar]) to treat pancreatic cancer that has spread to nearby tissues or to other parts of the body and cannot be treated with surgery. Erlotinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells.
Receptor tyrosine kinases (RTKs), the protein kinases which catalyse phosphorylation of hydroxyl groups on tyrosine residues, predominantly following activation by an extracellular ligand, have proved to be a particularly tractable class of drug target involved in a wide range of cellular signalling pathways. Inhibitors of protein kinases most commonly target the ATP binding site of the activated kinase, although binding to an adjacent allosteric site or to an inactive form of the kinase has also been exploited.


Regulatory approval followed for imatinib (GLEEVEC™), gefitinib (IRESSA ™) and erlotinib (TARCEVA™)[1], the first small molecule signal transduction inhibitors, and for the proteasome inhibitor bortezomib (VELCADE ™) [2]. Like monoclonal antibodies, clinical studies with these drugs are providing tumour profiling data from which better understanding of the role of genetic factors in determining patient response is starting to emerge [35]. Clinical experience is also beginning to fulfil the anticipation that these targeted agents could offer a more manageable side-effect profile than cytotoxic therapy In the case of gefitinib, an inhibitor of the EGF signalling pathway which regulates tumour cell growth and survival, objective responses were observed in phase II and III monotherapy in 10–20% of patients with advanced refractory non-small cell lung cancer, but no significant additive effects were seen in first line phase III trials in combination with chemotherapy [3]. More recent work has, however, provided evidence that mutations in the EGF receptor appear to confer increased sensitivity to inhibition by gefitinib [4]

1.Imatinib: A Breakthrough of Targeted Therapy in Cancer //Nida Iqbal and Naveed Iqbal
2. Inhibiting the immunoproteasome's β5i catalytic activity affects human peripheral blood‐derived immune cell viability// Katrien Pletinckx, Silke Vaßen, Ilka Schlusche, Sonja Nordhoff, Gregor Bahrenberg, and Torsten R. Dunkern
3. Cancer//edited by Rob Bradbury
4.Mutations in the epidermal growth factor receptor (EGFR) gene in triple negative breast cancer: possible implications for targeted therapy //Yvonne Hui-Fang Teng, Wai-Jin Tan, Aye-Aye Thike, Poh-Yian Cheok, Gary Man-Kit Tse,Nan-Soon Wong,3 George Wai-Cheong Yip,Boon-Huat Bay,and Puay-Hoon Tan
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).

Chemical structure of Erlotinib-EGFR dimer with indication of key amino acid residues

Chemical structure of Erlotinib

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Chemical structure of erlotinib molecule showing atoms and charges
Erlotinib binds with a very similar affinity to wild-type and L834R-mutated EGFR-TKD. [Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain ] L834Rmutated NSCLC tumours respond to first-generation TKIs (like erlotinib)


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.

Results of numerical calculations and comparison with the obtained experimental data

The first graph (red) shows the dependence of the value IC50 on the mutation in the EGFR protein, the second graph (blue) shows the results of the calculations using the software developed by us, which shows the direction of the change in affinity for mutations in proteins
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The experimental values were taken [In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer]

1. Thus, the numerical method developed by us makes it possible to determine the range of changes in the stability of dimeric complexes with the participation of a small chemical molecule and a protein molecule.

2. Application of our method will allow us to identify mutations that lead to a decrease in the affinity of components.

3. Numerical analysis requires a three-dimensional structure of the dimer under study, in the protein component of which substitutions of amino acid residues will be introduced.

Examples using small molecules are given below

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