1st International Conference on Chemo and BioInformatics, ICCBIKG 2021, (410-413)
AUTHOR(S) / АУТОР(И): Nemanja Djokovic, Ana Postolovic, Katarina Nikolic
E-ADRESS / Е-АДРЕСА: nemanja@pharmacy.bg.ac.rs, anap997@gmail.com, knikolic@pharmacy.bg.ac.rs
DOI: 10.46793/ICCBI21.410DJ
ABSTRACT / САЖЕТАК:
The group of 5‐[(amidobenzyl)oxy]‐nicotinamides represents promising group of sirtuin 2 (SIRT2) inhibitors. Despite structural similarity, representatives of this group of inhibitors displayed versatile mechanisms of inhibition which hamper rational drug design. The aim of this research was to form a 3D-QSAR (3D-Quantitative Structure-Activity Relationship) model, define the pharmacophore of this subgroup of SIRT2 inhibitors, define the mode of protein-ligand interactions and design new compounds with improved predicted activity and pharmacokinetics. For the 3D-QSAR study, data set was generated using structures and activities of 166 5‐[(amidobenzyl)oxy]‐nicotinamides. 3D-conformations of compounds were optimized, alignment-independent GRIND2 descriptors were calculated and 3D-QSAR PLS models were generated using 70% of data set. To investigate bioactive conformations of inhibitors, molecular docking was used. Molecular docking analysis identified two clusters of predicted bioactive conformations which is in alignment with experimental observations. The defined pharmacophoric features were used to design novel inhibitors with improved predicted potency and ADMET profiles.
KEY WORDS / КЉУЧНЕ РЕЧИ:
3D-QSAR, molecular docking, SIRT2 inhibitors, pharmacophore, ADMET
REFERENCES / ЛИТЕРАТУРА:
- M. Schiedel, D. Robaa, T. Rumpf, W. Sippl, and M. Jung, The Current State of NAD+- Dependent Histone Deacetylases (Sirtuins) as Novel Therapeutic Targets, Med. Res. Rev., vol. 38, no. 1, pp. 147–200, 2018.
- D. Ruzic, N. Djokovic, K. Nikolic, and Z. Vujić, Medicinal chemistry of histone deacetylase inhibitors, Arh. Za Farm., vol. 71, no. 2, pp. 73–100, 2021, doi: 10.5937/arhfarm71-30618.
- T. Ai, D. J. Wilson, S. S. More, J. Xie, and L. Chen, 5-((3-Amidobenzyl)oxy)nicotinamides as Sirtuin 2 Inhibitors, J. Med. Chem., vol. 59, no. 7, pp. 2928–2941, Apr. 2016, doi: 10.1021/acs.jmedchem.5b01376.