Version 1
: Received: 27 February 2022 / Approved: 28 February 2022 / Online: 28 February 2022 (08:40:24 CET)
How to cite:
Yazdani, B.; A.C. Wing, P.; J. Enguita, F.; Sirous, H. Identification of Novel Direct Small-Molecule Inhibitors against HIF-2A using Structure-based Virtual Screening and Molecular Dynamics Simulation. Preprints2022, 2022020349. https://doi.org/10.20944/preprints202202.0349.v1
Yazdani, B.; A.C. Wing, P.; J. Enguita, F.; Sirous, H. Identification of Novel Direct Small-Molecule Inhibitors against HIF-2A using Structure-based Virtual Screening and Molecular Dynamics Simulation. Preprints 2022, 2022020349. https://doi.org/10.20944/preprints202202.0349.v1
Yazdani, B.; A.C. Wing, P.; J. Enguita, F.; Sirous, H. Identification of Novel Direct Small-Molecule Inhibitors against HIF-2A using Structure-based Virtual Screening and Molecular Dynamics Simulation. Preprints2022, 2022020349. https://doi.org/10.20944/preprints202202.0349.v1
APA Style
Yazdani, B., A.C. Wing, P., J. Enguita, F., & Sirous, H. (2022). Identification of Novel Direct Small-Molecule Inhibitors against HIF-2A using Structure-based Virtual Screening and Molecular Dynamics Simulation. Preprints. https://doi.org/10.20944/preprints202202.0349.v1
Chicago/Turabian Style
Yazdani, B., Francisco J. Enguita and Hajar Sirous. 2022 "Identification of Novel Direct Small-Molecule Inhibitors against HIF-2A using Structure-based Virtual Screening and Molecular Dynamics Simulation" Preprints. https://doi.org/10.20944/preprints202202.0349.v1
Abstract
The main regulatory factors during the adaptation of cancer cells to hypoxic stress are the hypoxia-inducible factors (HIFs), which are being increasingly recognized as an interesting and challenging target for the design of new chemotherapeutic molecules. HIF2A was found to have an large internal hydrophilic cavity within its PAS-B domain, unique to this sub-unit and is suggested to be a possible ligand-binding site. Regulation of HIF2A by cellular molecules is still greatly unknown. In This paper we have employed in-silico techniques, such as molecular docking and dynamic simulation, to design new direct inhibitors against HIF-2A subunit via targeting one of its critical domains and the final top screened molecules have been tested on hypoxic cancer cells for further validation of their inhibitory potential. we targeted the hydrophilic cavity inside the PAS-B domain of the HIF2A to identify novel molecules with a high binding capacity. Virtual Screening methodology was used for molecular docking of NSC library against the target domain inside the HIF2A PAS-B domain with the top 5% compounds with significant MolDock and Re-rank scores were selected for further analysis. The NSC 106416, NSC 217021, NSC 217026, and NSC 215639 compounds were selected based on their docking scores. NSC 215639 had the minimum polar solvation energy and also had a relative strong binding energy. NSC 217026 had the strongest binding energy among other compounds.
Keywords
Hypoxia-inducible factor; cancer; hypoxia; drug discovery; medicinal chemistry; virtual screening; molecular dynamics simulation; MM-PBSA; Drug discovery
Subject
Medicine and Pharmacology, Pharmacology and Toxicology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
