Activity and in silico guided design of bioactive small molecules – ADESIRE
Head: Prof Tomica Hrenar, PhD
Duration: 1 Mar 2017-28 Feb 2021
In this project synthesis, characterization, and biological evaluation of novel types of compounds including extensive quantum chemical calculations and multi-way analyses is proposed. Bioactive chemical scaffolds such as benzimidazoles, imidazoles, and quinuclidines are recognized as compounds with a broad spectrum of biological activities also in the fields of infectious diseases and central nervous system disorders (Alzheimer’s disease, AD). We envisioned that further exploration of these chemical classes can result with the identification of new leads suitable for further development into potential hits. As a highly innovative part of this study, advanced methods of molecular modelling combined with multi-way analysis will be used for construction of accurate quantitative structure–activity relationship models. These models will be used for iterative procedure of guided rational design. Initially, new bioactive compounds will be synthesized using classical and contemporary methods of organic chemistry. Chiral compounds will be prepared and the stereoselectivity of interactions evaluated. For all compounds, antimicrobial activity will be estimated targeting resistance genes to treat infections caused by multidrug-resistant Gram-negative bacteria. Furthermore, their perspective for development of enhanced anti-AD drugs will be assessed by determining their inhibitory potency toward cholinesterases. To evaluate possible beneficial synergistic effects, hybrid molecules as well as various combinations of the most active synthesized compounds will be prepared and tested. Molecular modelling, docking studies and a newly developed method for application of multi-way analysis to combined experimental and theoretical data will be used to direct structural changes leading to the synthesis of new, more efficient bioactive scaffolds with potential use in biotechnology, pharmaceutical industry and medicine.