Moshawih, Said and Goh, Hui Poh and Kifli, Nurolaini and Darwesh, Mohammed Abd ElFattah and Ardianto, Chrismawan and Goh, Khang Wen and Long, Chiau Ming * (2023) Identification and optimization of TDP1 inhibitors from anthraquinone and chalcone derivatives: consensus scoring virtual screening and molecular simulations. Journal of Biomolecular Structure and Dynamics, 11 (1). ISSN 1538-0254
Full text not available from this repository. (Request a copy)Abstract
Virtual screening aims to identify and rank compounds with drug/lead-like properties based on their affinity for the protein target. We developed a methodology that integrates structure- and ligand-based screening approaches to enhance hit rates against the TDP1 protein within a database of anthraquinone and chalcone derivatives, followed by evaluation of prioritized compounds through molecular simulations. This technique is particularly useful for training set imbalances. Four screening methods were used: QSAR, pharmacophore, shape similarity, and docking. Each method was individually trained to score compounds, and the scores were fused to create parallel Z-score fusion. The QSAR models exhibited satisfactory R2 values (0.84 to 0.75), whereas the pharmacophoric and shape similarity models demonstrated excellent performance (ROC:0.82–0.88). Docking enrichment analysis identified 6N0D as the optimal TDP1 crystal structure (ROC = 0.73). Remarkably, the consensus scoring method surpassed other screening methods, achieving the highest ROC value of 0.98. Docking screening prioritized compounds with binding modes resembling the co-crystallized ligands, whereas MMGBSA, consensus, and docking produced dynamic simulations that were as stable as the co-crystallized ligands. Additionally, the QSAR-selected compounds exhibited binding modes similar to those of commercially available TDP1 inhibitors. In this study, a strong correlation was found between the inhibitory concentrations and binding energy values of commercialized TDP1 inhibitors, indicating that the top-ranked compounds are expected to have potent inhibitory effects in the nano-/micromolar range. The results of this study establish that consensus scoring can be used as an adaptable mainstay virtual screening methodology, pending subsequent experimental validation for affirmation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | consensus scoring; docking; virtual screening; TDP1; molecular mechanics; |
| Subjects: | Q Science > QH Natural history Q Science > QP Physiology R Medicine > RS Pharmacy and materia medica |
| Divisions: | Others > Non Sunway Academics Sunway University > School of Medical and Life Sciences [formerly School of Healthcare and Medical Sciences until 2020] > Dept. of Medical Education [formerly Dept. of Allied Healthcare until 2023] |
| Depositing User: | Ms Yong Yee Chan |
| Related URLs: | |
| Date Deposited: | 24 Jul 2024 01:51 |
| Last Modified: | 24 Jul 2024 01:51 |
| URI: | http://eprints.sunway.edu.my/id/eprint/2860 |
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