2. Academic Validation
  3. Identification of small molecular inhibitors of SIRT3 by computational and biochemical approaches a potential target of breast cancer

Identification of small molecular inhibitors of SIRT3 by computational and biochemical approaches a potential target of breast cancer

  • Sci Rep. 2024 May 30;14(1):12475. doi: 10.1038/s41598-024-63177-7.
Atta Ullah # 1,  Najeeb Ur Rehman # 1,  Waseem Ul Islam 2,  Faizullah Khan 1,  Muhammad Waqas 1,  Sobia Ahsan Halim 3,  Afnan Jan 4,  Abdullatif Bin Muhsinah 5,  Ajmal Khan 6,  Ahmed Al-Harrasi 7
Affiliations

Affiliations

  • 1 Natural and Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mauz, PO Box 33, Nizwa, Oman.
  • 2 Department of Pharmacy, University of Swabi, Khyber Pakhtunkhwa, Pakistan.
  • 3 Natural and Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mauz, PO Box 33, Nizwa, Oman. [email protected].
  • 4 Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Mecca, Kingdom of Saudi Arabia.
  • 5 Department of Pharmacognosy, College of Pharmacy, King Khalid University, 61441, Abha, Saudi Arabia.
  • 6 Natural and Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mauz, PO Box 33, Nizwa, Oman. [email protected].
  • 7 Natural and Medical Sciences Research Center, University of Nizwa, 616 Birkat Al Mauz, PO Box 33, Nizwa, Oman. [email protected].
  • # Contributed equally.
PMID: 38816444 DOI: 10.1038/s41598-024-63177-7
Abstract

Sirtuin 3 (SIRT3) belongs to the Sirtuin protein family, which consists of NAD+-dependent lysine deacylase, involved in the regulation of various cellular activities. Dysregulation of SIRT3 activity has been linked to several types of Cancer, including breast Cancer. Because of its ability to stimulate adaptive metabolic pathways, it can aid in the survival and proliferation of breast Cancer cells. Finding new chemical compounds targeted towards SIRT3 was the primary goal of the current investigation. Virtual screening of ~ 800 compounds using molecular docking techniques yielded 8 active hits with favorable binding affinities and poses. Docking studies verified that the final eight compounds formed stable contacts with the catalytic domain of SIRT3. Those compounds have good pharmacokinetic/dynamic properties and gastrointestinal absorption. Based on excellent pharmacokinetic and pharmacodynamic properties, two compounds (MI-44 and MI-217) were subjected to MD simulation. Upon drug interaction, molecular dynamics simulations demonstrate mild alterations in the structure of proteins and stability. Binding free energy calculations revealed that compounds MI-44 (- 45.61 ± 0.064 kcal/mol) and MI-217 (- 41.65 ± 0.089 kcal/mol) showed the maximum energy, suggesting an intense preference for the SIRT3 catalytic site for attachment. The in-vitro MTT assay on breast Cancer cell line (MDA-MB-231) and an apoptotic assay for these potential compounds (MI-44/MI-217) was also performed, with flow cytometry to determine the compound's ability to cause Apoptosis in breast Cancer cells. The percentage of apoptotic cells (including early and late apoptotic cells) increased from 1.94% in control to 79.37% for MI-44 and 85.37% for MI-217 at 15 μM. Apoptotic cell death was effectively induced by these two compounds in a flow cytometry assay indicating them as a good inhibitor of human SIRT3. Based on our findings, MI-44 and MI-217 merit additional investigation as possible breast Cancer therapeutics.

Keywords

Breast cancer; Flow cytometry; Inhibitor; MTT assay; Molecular docking; SIRT3.

Figures
Products