2nd International Conference on Chemo and Bioinformatics ICCBIKG 2023 (641-644)
АУТОР(И) / AUTHOR(S): Milan P. Mladenović, Nevena M. Tomašević, Sanja Lj. Matić, Tamara M. Mladenović, Rino Ragno
Е-АДРЕСА / E-MAIL: milan.mladenovic@pmf.kg.ac.rs
DOI: 10.46793/ICCBI23.641M
САЖЕТАК / ABSTRACT:
Computational medicinal chemistry, if used properly and in accordance with the available experimental data, may provide significant support to rational drug design. Herein, an overview of the computational approaches that have been applied to an estrogen receptor α (ERα) and endowed in the rational design of pM ERα antagonists with profound anti-breast cancer activity either in vitro or in vivo, will be presented. ERα is a 17β-estradiol inducible transcriptional regulator that initiates the RNA polymerase II-dependent transcriptional machinery, pointed for breast cancer (BC) development via either genomic direct or genomic indirect (i.e., tethered) pathway. To develop innovative ligands, structure-based (SB) 3-D QSAR, ComBinE, and 3-D Pharmacophore studies have been undertaken from experimentally resolved partial agonists, SERMs, and SERDs within either wild-type or mutated ERα receptors. SB and ligand-based (LB) alignments gave rules to align the untested compounds. The protocols led to the development of 3DQs, CBEs, and 3DPQs compounds, further synthesized and submitted to either in vitro or in vivo assessments, upon which new leads were revealed as candidates for clinical trials.
КЉУЧНЕ РЕЧИ / KEYWORDS:
ERα, 3-D QSAR, COMBINE, 3-D Pharmacophore, SB and LB alignment assessment, rational design of new SERMs, synthesis, pharmacological evaluation in vitro and in vivo
ЛИТЕРАТУРА / REFERENCES:
- N. Kurtanović, N. Tomašević, S. Matić, M.M. Mitrović, D.A. Kostić, M. Sabatino, Lorenzo Antonini, R. Ragno, M. Mladenović., Human estrogen receptor α antagonists, part 1: 3-D QSAR driven rational design of innovative coumarin-related antiestrogens as breast cancer suppressants through structure-based and ligand-based studies, Journal of Chemical Information and Modeling, 61 (2021) 5028-5053.
- N. Kurtanović, N. Tomašević, S. Matić, M.M. Mitrović, D.A. Kostić, M. Sabatino, Lorenzo Antonini, R. Ragno, M. Mladenović., Human estrogen receptor α antagonists, part 2: synthesis driven by rational design, in vitro antiproliferative, and in vivo anticancer evaluation of innovative coumarin-related antiestrogens as breast cancer suppressants, European Journal of Medicinal Chemistry, 227 (2022) 113869.
- N. Kurtanović, N. Tomašević, S. Matić, E. Proia, M. Sabatino, L. Antonini, M. Mladenović, R. Ragno., Human estrogen receptor alpha antagonists, part 3: 3-D Pharmacophore and 3-D QSAR guided brefeldin a hit-to-lead optimization toward new breast cancer suppressants, Molecules, 27 (2022)