Creation of new medical drugs based on TRIZ and computer mathematical modeling
Ключові слова:
TRIZ, theory of inventive problem solving, Altshuller, TRIZ in pharmaceutical industry and pharmacology, Laws of technical systems evolution, problem solving, Su-field analysis, drug-design, dynamic self-organizing, quasi live drugs, anticancer, antiviral, multidrug bacterial resistance, antibacteriАнотація
The article provides an overview of the current state of the use of TRIZ in the pharmaceutical industry and our R&D efforts in that area, based on TRIZ and computer mathematical modeling. Drug development is one of the most important research areas, which affects almost every family, and each one of us. However, nobody in the world has used TRIZ as a philosophy of solving problems in such important area as pharmaceutical research and development to develop new efficient medical drugs. The application of the principles of TRIZ in this arena opens up broad prospects in the creation of new classes of drugs that can independently adapt to the patient's body. The combination of contradictions, laws of development systems, algorithms, Su-field analysis, TRIZ principles, deep fundamentals of pharmaceutical industry and pharmacology, modern computer mathematical modeling, in the solution of each of the tasks at once, allows us to achieve extraordinary results and obtain significantly more effective novel drugs. For the first time in the World we have developed dynamic self-organizing, quasi live drugs, based on the principles of TRIZ and computerized mathematical modeling. These are drugs capable of adapting independently both to the human body and to molecular targets, including viruses, cancer cells and microorganisms. We have created 17 new projects, however, in this article we illustrate just 6 examples from our research and developments: 1. Novel directions to fight multidrug resistant microorganisms. 2. Polymyxin with reduced nephrotoxicity. 3. Dynamic drugs: Dynamic insulin. 4. Dynamic drugs: The dynamic anticancer drug Target-R to treat different cancers. 5. Dynamic drugs: Dynamic antiviral drug Albuvir. 6. Dynamic drugs: Hemostatic Gemma. Applying TRIZ and mathematical modeling in pharmaceutical industry, produces novel and future R&D trends. The proposed new paradigm of combating infectious diseases using TRIZ led to the creation of a unique pharmaceutical composition. The molecular modeling approach led to the intensification of research and for synthesis of drugs based on simulated inhibitor profiles. This increased the yield of novel dynamic drugs. The dynamic drugs can overcome many problems from resistance to the slippage effect, to eliminate the side effects of drugs. This will save millions of lives. We deeply integrated TRIZ and computer mathematical modeling in our R&D. In addition, our approach includes the application of the laws of quantum physics and quantum chemistry; additionally, knowledge of the behavior of molecules in different solutions and their interaction with each other at different temperatures, in the presence of salts and other compounds. Really effective drugs can be developed only on the basis of a systematic approach and in-depth knowledge in the fields of medical, pharmaceutical physical chemistry, analytical chemistry and pharmacognosy, chemistry of natural compounds, plant medicine technology, biochemistry and molecular biology, pharmacology and many other disciplines. Modeling these processes requires a large amount of not only computer time, but also knowledge in a number of broad areas: from quantum physics and chemistry to synthetic organic chemistry, in order to synthesize engineered substances. Despite changes in the concept of drug development: from banal screening (out of thousands of synthesized compounds, only one showed biological activity) to those obtained as a result of molecular modeling (another name is drug-design). (named as drug-design). The approach with the use of molecular modeling led to the intensification of research - to the synthesis of drugs based on simulated inhibitor profiles. This increased the yield of drugs - out of every hundreds of the synthesized substances, one showed the expected activity. The cost of pharmaceutical development software is currently quite high and can even reach tens of millions of dollars. But this is a reasonable amount, which makes it possible to obtain the required pharmaceutical preparations, at least for known target proteins. However, for the design of drugs of new generations at all stages of development - from building a model of a target protein to creating a drug profile and its synthesis, TRIZ has not been used systematically. Pharmaceutical industry is a huge area to be explored by TRIZ.
Посилання
Altshuller G. S. The innovation algorithm: TRIZ, systematic innovation and technical creativity. – Technical Innovation Center, Inc. 1999.320 P. 2
Altshuller G., Altov G., Altov H. And suddenly the inventor appeared: TRIZ, the theory of inventive problem solving. – Technical Innovation Center, Inc. 1996. 171 P.
Altshuller G., Zlotin B., Zusman A., Philatov V. Tools of Classical TRIZ. Ideation International Inc. 1999.
Farber B.S. Methods for solving macro-level problems in TRIZ. Methodology and methods of technical creativity. Academy of Sciences of the USSR, Novosibirsk 1984. p. 76-78
Farber BS., Nikitin N.G. Prediction of the structures of the knee mechanisms using the Laws of Development of Technical Systems and the formulation of the problem for their development based on the Functional Cost Analysis. Methodology and methods of technical creativity. Academy of Sciences of the USSR. Novosibirsk 1984 p. 122-125
Farber B.S. The reversibility of some laws of the development of technical systems. In the collection of reports of the All-Union USSR Conference: "Theory and practice of teaching inventive creativity". Chelyabinsk. 1988.
Farber, B. S. Development of methods for improving the system "man-prosthesis (orthosis) -environment", Peter the Great St. Petersburg Polytechnic University, St. Petersburg,1992, 43 p
Farber B.S. Dynamics of pavement. BYU 04427. Kiev. 1976. 55 P.
Farber B.S, Prokopchuk Y.A. Problems of development of a package of computer applied modeling programs. VINITI 6972-889. 1989
Farber B.S. Features of the application of the laws of development of technical systems in biotechnical systems. In the collection of reports of the All-Union USSR Conference: "Theory and practice of teaching inventive creativity". Chelyabinsk. 1988. P. 75-77.
Farber B.S., Moreinis I.S. Biomechanical basis of choosing the rational mass and its distribution throughout the lower limb prosthesis segments. J of Rehabilitation Research and Development.1995. Vol. 32 N. 4. P. 325-336
Farber B.S, Jacobson J.S. An above-knee prosthesis with a system of energy recovery//. J of Rehabilitation Research and Development. 1995. Vol. 32. N. 4. P. 337-348
Farber B.S. Features of the application of the laws of development of technical systems in biotechnical systems. In the collection of reports of the All-Union USSR Conference: "Theory and practice of teaching inventive creativity". Chelyabinsk. 1988. P. 75-77.
Farber B.S. Theoretical prerequisites for the synthesis of new technical solutions in bioengineering. Series "Prosthetics and Prosthetic Design", Central Scientific Research Institute of Prosthetics and Orthotics. Issue 3. Moscow. 1989. 22 P.
Farber B.S., Vitenzon A.S., Moreinis I.S. Theoretical foundations of the construction of lower limb prostheses and movement correction: / Editor. B.S. Farber. Moscow: Central Scientific Research Institute of Prosthetics and Orthotics. CNIIP. 1994. 2347 P.
Barber M. Coagulase‐positive staphylococci resistant to penicillin //The Journal of Pathology and Bacteriology. – 1947. Т. 59. №. 3. С. 373-384.
Freeman V. J. Studies on the virulence of bacteriophage-infected strains of Corynebacterium diphtheriae //Journal of bacteriology. 1951. Т. 61. №. 6. С. 675.
Lee, J. H., Wang, T., Ault, K., Liu, J., Schmitt, M. P., & Holmes, R. K. Identification and characterization of three new promoter/operators from Corynebacterium diphtheriae that are regulated by the diphtheria toxin repressor (DtxR) and iron. Infection and immunity. 1997. Vol.65. N. 10. P. 4273-4280.
Kwaszewska A. K., Brewczynska A., Szewczyk E. M. Hydrophobicity and biofilm formation of lipophilic skin corynebacteria //Polish journal of microbiology. 2006. Т. 55. №. 3. P. 189-193.
Davies D. Understanding biofilm resistance to antibacterial agents //Nature reviews Drug discovery. 2003. Т. 2. N. 2. P. 114.
Anderl J. N., Franklin M. J., Stewart P. S. Role of antibiotic penetration limitation in Klebsiella pneumoniae biofilm resistance to ampicillin and ciprofloxacin //Antimicrobial agents and chemotherapy. 2000. Vol. 44. №. 7. P. 1818-1824.
Anderl J. N., Franklin M. J., Stewart P. S. Role of antibiotic penetration limitation in Klebsiella pneumoniae biofilm resistance to ampicillin and ciprofloxacin //Antimicrobial agents and chemotherapy. 2000. Vol. 44. – №. 7. P. 1818-1824.
Martínez J. L. Antibiotics and antibiotic resistance genes in natural environments //Science. 2008. Vol. 321. N. 5887. – P. 365-367.
Jackson N., Czaplewski L., Piddock L. J. V. Discovery and development of new antibacterial drugs: learning from experience? //Journal of Antimicrobial Chemotherapy. 2018. Vol. 73. N. 6. P. 1452-1459.
Hartmann R., et al. Emergence of three-dimensional order and structure in growing biofilms. Nature Physics. 2018. Vol.1.
Nadell C. D., Drescher K., Wingreen N. S., Bassler B. L. Extracellular matrix structure governs invasion resistance in bacterial biofilms// The ISME journal. 2015. Vol.9. N. 8. P. 1700.
Taglialegna A., Lasa I., Valle J. Amyloid structures as biofilm matrix scaffolds //Journal of bacteriology. 2016. Vol. 198. N. 19. P. 2579-2588.
Moussa F. Z. B., Rasovska I., Dubois S., De Guio R., Benmoussa, R. Reviewing the use of the theory of inventive problem solving (TRIZ) in green supply chain problems// Journal of cleaner production. 2017. Vol.142. P. 2677-2692.
Casner D., Livotov P., da Silva P. K. (). TRIZ-Based Approach for Process Intensification and Problem Solving in Process Engineering: Concepts and Research Agenda. In Advances and Impacts of the Theory of Inventive Problem Solving.2018. (P. 217-229). Springer, Cham.
Newell D. G., Manning G., Goldberg M., Morgan D., Wassenaar T. M. The Influence of Virulence Factors on Dose Response of Food-Borne Pathogens. In Foodborne Pathogens. 2017. P. 531-552. Springer. Cham.
Lobato-Márquez D., Díaz-Orejas R., Garcia-del Portillo F. Toxin-antitoxins and bacterial virulence //FEMS microbiology reviews. 2016. Vol. 40. N. 5. P. 592-609.
Martynov A., Osolodchenko T., Farber B., Farber S. Influence Of Non-Metabolic Microbial Growth Promotors (AMP Activators) On The Sensitivity To Antimicrobials In The Actually Multiresistant Microbial Strains. bioRxiv, 2017.143438.
Beuchat L. R. Influence of water activity on sporulation, germination, outgrowth, and toxin production //Water Activity. Routledge. 2017. P. 137-151.
Patent application WO2013100792A1 Method for accelerating bacterial biomass growth and attenuating the virulence of bacteria. Martynov AV, Farber BS, Farber SB
Rankin G. O., Valentovic M. A. Historical Perspective of Nephrotoxicity //Toxicological Sciences. 2018. Vol. 164. №. 2. P. 377-378.
Thomas R., et al. The use of polymyxins to treat carbapenem resistant infections in neonates and children. Expert Opinion on Pharmacotherapy. 2018. 1-8.
Weber E. J., et al. (). Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity. JCI insight. 2018. Vol.3, N. 24.
Chou J. R., Ha J. L. Coupling Products and Services in Design Processes: A Case Study of Smart Drip. KnE Social Sciences. 2018. Vol. 3. N.10.
Petrov V. Fundamentals of TRIZ: Theory of Inventive Problem Solving / Publishing solutions, 2018. - 720 p.
Fiorineschi L., Frillici F. S., Rotini F., Tomassini M. (). Exploiting TRIZ Tools for enhancing systematic conceptual design activities. Journal of Engineering Design. 2018.1-32.
De Portu S, et al.. The pharmacoeconomic impact of amlodipine use on coronary artery disease. Pharmacol Res. 2006. Vol.54. N. 2. P.158-163.
Malcolm R, et al. A controlled trial of amlodipine for cocaine dependence: a negative report. J Subst Abuse Treat. 2005. Vol.28. N.2. P. 197-204.
Bigler J. et al. Polymorphisms predicted to alter function in prostaglandin E2 synthase and prostaglandin E2 receptors. Pharmacogenet Genomics. 2007.Vol. 17, N.3. P.221-227
Kreek M.J., Laforge K.S. Stress responsivity, addiction, and a functional variant of the human mu-opioid receptor gene. Mol Interv. 2007. Vol.7. N 2. P.74-78.
Jaillon P, Simon T. Genetic polymorphism of beta-adrenergic receptors and mortality in ischemic heart disease. Therapie. 2007.Vol.62. N.1.P. 1-7.
Riddy D. M., et al. G Protein–coupled receptors targeting insulin resistance, obesity, and type 2 diabetes mellitus. Pharmacological reviews.2018. Vol.70. N.1. P. 39-67.
Livotov P., et al. Systematic Innovation in Process Engineering: Linking TRIZ and Process Intensification. In Advances in Systematic Creativity. 2019. P.27-44) Palgrave Macmillan, Cham.
Patent application WO2013100793A1 Insulsin derivative with antihyperglycemic activity and method for the production thereof. Martynov AV, Farber BS, Farber SB
Nosalskaya T. N., Bomko T. V., Martynov A. V., Farber B. S., Farber S. B. Oral long-acting pharmaceutical form of insulin on the basis of self-organizing quasi-living system of combinatorial peptides. Annals of Mechnikov Institute. 2015. Vol.2. N. 1. P. 64-70.
Tomasetti C., Li L., Vogelstein B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science. 2017. Vol.355. N.6331. P. 1330-1334.
Liu F. S. Mechanisms of chemotherapeutic drug resistance in cancer therapy—a quick review //Taiwanese Journal of Obstetrics and Gynecology. 2009. Vol. 48. N. 3. P. 239-244.
Postow M. A., Callahan M. K., Wolchok J. D. Immune checkpoint blockade in cancer therapy. Journal of clinical oncology. 2015. Vol.33. N. 17. P. 1974.
Partridge A. H., Burstein H. J., Winer E. P. Side effects of chemotherapy and combined chemohormonal therapy in women with early-stage breast cancer. JNCI Monographs. 2001. N.30. P. 135-142.
Fidler I. J., Blach C. M. The biology of cancer metastasis and implications for therapy. Current problems in surgery. 1987. Vol.24. N.3. P. 137-209.
Godfrey D. I., et al. Unconventional T cell targets for cancer immunotherapy. Immunity. 2018. Vol. 48. N.3. P. 453-473.
June C. H., et al. CAR T cell immunotherapy for human cancer. Science. 2018. Vol.359. N. 6382. P.1361-1365.
Zhang T., et al. Polysialic acid-polyethylene glycol conjugate-modified liposomes as a targeted drug delivery system for epirubicin to enhance anticancer efficiency. Drug delivery and translational research. 2018. Vol. 8. N.3. P. 602-616.
Olusanya T., et al. Liposomal drug delivery systems and anticancer drugs. Molecules. 2018. Vol.23. N.4. P. 907.
Bhowmik S., et al. Two multicenter Phase I randomized trials to compare the bioequivalence and safety of a generic doxorubicin hydrochloride liposome injection with Doxil or Caelyx in advanced ovarian cancer. Cancer chemotherapy and pharmacology. 2018. Vol. 82. N. 3. P. 521-532.
Maiti K., et al. (). Comparison of Physicochemical Properties of Generic Doxorubicin HCl Liposome Injection with the Reference Listed Drug. Anti-Cancer Agents in Medicinal Chemistry. 2018. (Formerly Current Medicinal Chemistry-Anti-Cancer Agents). Vol. 18. N. 4. P. 597-609.
Lopez A., Liu J. DNA Oligonucleotide-Functionalized Liposomes: Bioconjugate Chemistry, Biointerfaces, and Applications //Langmuir. 2018. Vol. 34. N. 49. P. 15000-15013.
Ghoshal K., Jacob S. T. An alternative molecular mechanism of action of 5-fluorouracil, a potent anticancer drug. Biochemical pharmacology. 1997. Vol. 53. N. 11. P. 1569-1575.
Holmlund J. T., Monia B. P., Kwoh T. J., Dorr F. A. Toward antisense oligonucleotide therapy for cancer: ISIS compounds in clinical development. Current opinion in molecular therapeutics. 1999. Vol.1. N.3. P. 372-385.
Rico A. Chemo-defense system. Comptes Rendus de l'Académie des Sciences-Series III-Sciences de la Vie. 2001. Vol. 324. N. 2. P. 97-106.
Martynov A., Didenko G., Farber B., Farber S., Cruts, O. The anticancer activity of antisense micro RNA (fRNA) in combination with the lectin from Bacillus subtilis B‐7025. Journal of Pharmacy and Pharmacology. 2018. Vol.70. N. 6. P. 732-739.
Lyubomirskiy A., Litvin S., Ikovenko S., Thurnes C., Adunka R., Trends of Engineering Systems Evolution: TRIZ Paths to Innovation. TRIZ Consulting Group, 2018. 126 p.
Martynov A., Farber B. S., Farber S. S. U.S. Patent Application No. 13/861,624. 2014
Martynov A. V., Babkin N., Zheynova, N. (). Antiviral activity of the albuvir in models vesicular stomatitis virus and human herpes virus type 1 in vitro. Scientific Bulletin of Lviv National University of Veterinary Medicine and Biotechnology named Gzhytsky.2011. Vol.2. N. 1. P. 181-184.
Zheynova N. M. Principles of specific prophylaxis of Marek's disease and bacterial diseases of various etiologies // Veterinary Medicine of Ukraine. 2014. №. 5. P. 13-14.
Albuvir, the First and Only New-Generation Anti-Viral Drug. https://slideplayer.com/slide/15110346/#
Martynov A., Farber B. S., Farber S. S. (2015). U.S. Patent Application No. 14/023,231.
Altshuller G., Alʹtov G., Altov H. And suddenly the inventor appeared: TRIZ, the theory of inventive problem solving. 1996.Technical Innovation Center, Inc.
Altshuller G. 40 principles: TRIZ keys to innovation (Vol. 1). 2002. Technical Innovation Center, Inc.
Kime, Patricia. "Study: 25% of War Deaths Medically Preventable.“ Military Times, 29 Mar. 2013. https://www.militarytimes.com/2013/03/29/study-25-of-war-deaths-medically-preventable/
Petrov V.M. TRIZ Laws of Systems Development. Ridero. 2018, 920 pages
Petrov V. The Theory of Inventive Problem Solving - TRIZ / M .: SOLON-Press, 2017. 364 pages.
Zlotin B.L., Zusman A.V. 3-68 Solution of research problems. - Kishenev: ISTC “Progress, Map Moldoveniaske, 1991. 204 P.
Altshuller G.S., Zlotin B.L., Zusman A.V., Filatov V.I. Search for new ideas - From intuition to technology. Kishinev. 1989. 381 P.
##submission.downloads##
Опубліковано
Як цитувати
Номер
Розділ
Ліцензія
Авторське право (c) 2019 Annals of Mechnikov's Institute
Ця робота ліцензованаІз Зазначенням Авторства – Некомерційна – Без Похідних 3.0 Міжнародна.