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Molecular dynamics, database screening, density functional and docking studies of novel RAR ligands in cancer
1Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil.
Abstract:
Due to the major challenge which cancer treatment and cure still imposes after many decades to the international scientific community, there is actually considerable interest in new ligands with increased bioactivity. We have focused on the retinoid acid receptor, which is considered an interesting target for drug design. In this work, we have carried out density functional geometry optimizations and different docking procedures. We have performed screening in a large database (hundreds of thousands of molecules which we optimized at the AM1 level) yielding a set of potential bioactive ligands. Two new ligands were selected and optimized at B3LYP/6-31G* level. A flexible docking program was used to investigate the interactions between the receptor and the new ligands. Molecular dynamics were performed in order to investigate the stability of the two ligands as well as the crystallographic RAR ligand inside the RAR active site. We also investigated the stability of all the main protein-ligand contacts. The parameters of the Rule of Five were investigated. The result of this work is compared with a crystallographic ligand of RAR. One of our theoretically bioactive new ligands indicates stronger and more polar and hydrophobic interactions with the receptor.
Insights
Researchers identified novel bioactive ligands for cancer treatment targeting the retinoid acid receptor (RAR). Computational methods revealed these new ligands exhibit stronger interactions than existing ones, offering potential for improved drug design.
Area of Science:
- Medicinal Chemistry
- Computational Drug Design
- Molecular Biology
Background:
- Cancer remains a significant global health challenge, driving the search for novel therapeutic agents.
- The retinoid acid receptor (RAR) is a promising target for developing new anti-cancer drugs due to its role in cellular regulation.
Purpose of the Study:
- To identify and computationally evaluate novel bioactive ligands for the retinoid acid receptor (RAR).
- To investigate the binding interactions and stability of potential new ligands within the RAR active site.
Main Methods:
- Density functional theory (DFT) geometry optimizations and AM1 level optimizations for large-scale database screening.
- Flexible docking simulations and molecular dynamics to assess ligand-receptor interactions and stability.
- Evaluation of ligand properties using the Rule of Five parameters.
Main Results:
- Screening of a large molecular database identified potential bioactive ligands for RAR.
- Two novel ligands were computationally optimized and their interactions with RAR were analyzed.
- The new ligands demonstrated stronger, more polar, and hydrophobic interactions compared to a crystallographic RAR ligand.
Conclusions:
- Computational approaches successfully identified promising new ligands for RAR.
- The designed ligands show enhanced binding characteristics, suggesting potential for improved cancer therapeutics.
- Further investigation into these novel ligands could lead to the development of more effective cancer treatments.