Related Experiment Video
Updated: Aug 14, 2026
14:32
Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates
Published on: February 27, 2016
Comparative Structure-Based Analysis of Predicted BZD9L1 Binding Modes Across Human Sirtuins
Yi Jer Tan1,2, Yeuan Ting Lee1, Chern Ein Oon1
1Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Penang 11800, Malaysia.
International Journal of Molecular Sciences
|August 13, 2026
Summary
This study investigates BZD9L1, a sirtuin (SIRT) inhibitor, across all human SIRT isoforms using computational modeling and experiments. Findings suggest BZD9L1 interacts with multiple SIRT isoforms, guiding future inhibitor development for cancer and other diseases.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Sirtuins (SIRTs) are NAD+-dependent enzymes crucial in cellular processes, but their conserved catalytic sites hinder selective inhibitor design.
- BZD9L1, a benzimidazole derivative, is a known inhibitor of SIRT1 and SIRT2, yet its interactions with other SIRT isoforms are not fully understood.
Purpose of the Study:
- To computationally model and experimentally assess the binding interactions of BZD9L1 across all seven human sirtuin isoforms (SIRT1-7).
- To provide structural hypotheses for BZD9L1 recognition by sirtuins and guide the development of isoform-selective inhibitors.
Main Methods:
- Utilized a structure-based modeling framework including homology modeling and molecular docking to predict BZD9L1 binding modes across SIRT1-7.
- Conducted targeted experimental assessments, including cellular assays (acetyl-SOD2 levels) and cell-free enzymatic assays (SIRT5 inhibition).
Main Results:
- Molecular docking predicted BZD9L1 binding to the cofactor-binding region of all SIRT isoforms, with conserved orientations but varying interaction networks (hydrogen bonds, pi-stacking, hydrophobic contacts).
- Cellular assays indicated BZD9L1 alters SIRT3-associated deacetylation in colorectal cancer cells.
- Cell-free assays showed no measurable SIRT5 inhibition under tested conditions, suggesting isoform-specific activity.
Conclusions:
- BZD9L1 interacts with multiple human sirtuin isoforms, albeit with distinct predicted binding features.
- The study provides structural insights and testable hypotheses for BZD9L1-sirtuin interactions, crucial for designing targeted cancer therapies.
Related Concept Videos
01:49Conserved Binding Sites
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
01:49Conserved Binding Sites
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally analyses the...
00:49Ligand Binding and Linkage
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
01:57Gene Families
Gene families consist of groups of genes proposed to have originated from a common ancestor. Typically these arise through events in which a gene or genes are mistakenly duplicated during cell division. Unlike their parent genes (which are subject to selection pressure to maintain function), these gene copies do not need to preserve their sequences and may evolve at a relatively faster rate.
Occasionally these regions can be adapted to take on new roles within the organism, becoming novel genes...
Occasionally these regions can be adapted to take on new roles within the organism, becoming novel genes...
02:04Covalently Linked Protein Regulators
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
These groups modify specific amino acids in a protein.
02:40Ligand Binding Sites
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...