Presentations

Development of heterocyclic compounds capable of inhibiting fibril formation of amyloid β-peptide

Shevelyova M.P., Deryusheva E.I., Dotsenko V.V.¹, Dolganov A.A.¹, Alikova V.D., Permyakov S.E., Litus E.A.

Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, 142290 Pushchino, Russia

¹Department of Organic Chemistry and Technologies, Kuban State University, 149 Stavropolskaya St., 350040 Krasnodar, Russia

Low-molecular-weight heterocyclic compounds have demonstrated therapeutic potential in preclinical studies for Alzheimer's disease (AD) due to their ability to inhibit early stages of amyloid β-peptide (Aβ) aggregation. Our work is devoted to the search for original nicotinonitrile derivatives for the development of new agents for the treatment and prevention of AD by inhibiting Aβ multimerization. Molecular docking estimates of the free energies of interaction between the two parent molecular scaffolds of this class of compounds, pyrido-1,2,4-triazine (P124) and pyrido-1,3,5-triazine (P135), with the monomeric and protofibrillar forms of Aβ were found to be –6.3 and –6.4 cal/mol, respectively. By selecting substituents of various natures, proven in the rational design of small-molecule drugs as functionally promising and low-toxic (alkyl, hydroxyl, ether, aromatic, halogen atoms, alkylamines), a panel of candidate compounds was compiled consisting of 20 derivatives of P124 and P135 (Der). Their geometry was optimized in the MM2 force field, and the molecular and physicochemical characteristics of the candidates were calculated. Using the molecular docking method, the free energies of formation of Der complexes with the monomeric and protofibrillar forms of Aβ were estimated. It was found that the introduction of certain substituents decreases the free energy of the complexes compared to the parent molecular scaffolds by up to –9 kcal/mol. It is predicted that the free energies of interaction of Der with protofibrillar Aβ are 2–3 kcal/mol lower than the binding energies of the same candidates with monomeric Aβ. Moreover, a correlation between interaction energies and candidate structural parameters such as molecular volume, flexibility, and aqueous solubility is observed. The most promising candidate compounds are subject to further experimental testing for their ability to inhibit Aβ multimerization in vitro.

• abstract in Russian (PDF)