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Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling,
Nihal AbdElmoniem1, Marwa H Abdallah1, Rua M Mukhtar1
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Wad Madani 21111, Sudan.
Abstract:
Breast cancer (BC) is one of the main types of cancer that endangers women's lives. The characteristics of triple-negative breast cancer (TNBC) include a high rate of recurrence and the capacity for metastasis; therefore, new therapies are urgently needed to combat TNBC. Dual targeting HDAC6 and Hsp90 has shown good synergistic effects in treating metastatic TNBC. The goal of this study was to find potential HDAC6 and Hsp90 dual inhibitors. Therefore, several in silico approaches have been used. An e-pharmacophore model generation based on the HDAC6-ligand complex and subsequently a pharmacophore-based virtual screening on 270,450 natural compounds from the ZINC were performed, which resulted in 12,663 compounds that corresponded to the obtained pharmacophoric hypothesis. These compounds were docked into HDAC6 and Hsp90. This resulted in the identification of three compounds with good docking scores and favorable free binding energy against the two targets. The top three compounds, namely ZINC000096116556, ZINC000020761262, and ZINC000217668954, were further subjected to ADME prediction and molecular dynamic simulations, which showed promising results in terms of pharmacokinetic properties and stability. As a result, these three compounds can be considered potential HDAC6 and Hsp90 dual inhibitors and are recommended for experimental evaluation.
Insights
This study identified three novel natural compounds as potential dual inhibitors for HDAC6 and Hsp90, offering new therapeutic strategies for metastatic triple-negative breast cancer (TNBC). These compounds show promise for experimental validation.
Area of Science:
- Oncology
- Medicinal Chemistry
- Computational Biology
Background:
- Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to its high recurrence and metastatic potential.
- Existing therapies for TNBC are limited, necessitating the development of novel treatment strategies.
- Dual targeting of HDAC6 and Hsp90 has demonstrated synergistic efficacy against metastatic TNBC.
Purpose of the Study:
- To identify novel small molecules capable of simultaneously inhibiting both HDAC6 and Hsp90.
- To explore potential therapeutic agents for metastatic TNBC through in silico drug discovery.
Main Methods:
- Generation of an e-pharmacophore model for HDAC6.
- Pharmacophore-based virtual screening of a large natural compound library (ZINC).
- Molecular docking, ADME prediction, and molecular dynamics simulations of top-ranked compounds.
Main Results:
- Virtual screening yielded 12,663 potential compounds, from which three were selected based on docking scores and binding energy.
- The identified compounds (ZINC000096116556, ZINC000020761262, ZINC000217668954) exhibited favorable predicted pharmacokinetic properties and stability.
- Molecular dynamics simulations confirmed the stability of the compound-target complexes.
Conclusions:
- Three natural compounds were identified as promising dual inhibitors of HDAC6 and Hsp90.
- These compounds represent potential candidates for further experimental investigation and development as therapies for metastatic TNBC.
- The study highlights the utility of in silico approaches in discovering novel anti-cancer agents.
