Related Experiment Video
Updated: Jun 10, 2025
Modeling an Enzyme Active Site using Molecular Visualization Freeware
Published on: December 25, 2021
Accelerated molecular dynamics study of the interaction mechanism between small molecule inhibitors and
Yanqi Sun1, Chaoyue Jia1, Shaolong Zhang1
1School of Physics and Electronics, Shandong Normal University, Jinan, 250358, China. liuxinguo@sdnu.edu.cn.
Abstract:
In 2020, cancer-related deaths reached 9.96 million globally, of which China accounted for 3 million, ranking first in the world. Phosphoglycerate mutase 1 (PGAM1) is a key metabolic enzyme in glycolysis, catalysing the conversion of 3-phosphoglycerate to 2-phosphoglycerate. Based on the excellent anticancer activity of PGMI-004A and HKB99, new small molecules with an anthraquinone core were synthesised to inhibit tumour growth. Developing small molecules with an anthraquinone core targeting PGAM1 may be an effective strategy for treating cancer. In this study, accelerated molecular dynamics (aMD) simulation, dynamic cross-correlation map (DCCM) calculation, principal component analysis (PCA) and free energy landscape (FEL) analysis were used to analyse conformational changes of PGAM1 caused by binding of inhibitors 8KX, 9HU and HKB. DCCM calculations and PCA showed that inhibitor binding significantly affected the kinetic behaviour of PGAM1 and conformational rearrangement of PGAM1. The binding ability and mechanism of 8KX, 9HU and HKB to PGAM1 were studied using the molecular mechanics generalised Born surface area (MM-GBSA) method. The results showed that compared with 8KX, the binding ability of 9HU and HKB to PGAM1 was enhanced by sulphonamide reversal and aminocarboxyl trifluoromethyl substitution. There were several hydrophobic interactions between inhibitors and PGAM1, providing significant contributions for inhibitor binding. Calculation of residue-based free energy decomposition revealed that F22, R90, Y92, L95, V112, W115, R116, V121, P123, P124, R191 and M206 were key residues of the PGAM1-inhibitor interaction and could be used as effective targets for designing drugs that inhibit the activity of PGAM1.
Insights
New small molecules targeting Phosphoglycerate mutase 1 (PGAM1) show promise for cancer treatment. Molecular simulations reveal key interactions and enhanced binding, identifying potential drug targets for inhibiting PGAM1 activity.
Area of Science:
- Biochemistry and Molecular Biology
- Computational Chemistry
- Drug Discovery
Background:
- Cancer remains a leading cause of death globally, with significant impact in China.
- Phosphoglycerate mutase 1 (PGAM1) is a critical enzyme in glycolysis, implicated in tumor growth.
- Anthraquinone-based small molecules have demonstrated anticancer potential by targeting PGAM1.
Purpose of the Study:
- To investigate the binding mechanisms and conformational changes of PGAM1 induced by novel inhibitors.
- To evaluate the efficacy of small molecules with an anthraquinone core in inhibiting PGAM1.
- To identify key residues involved in PGAM1-inhibitor interactions for future drug design.
Main Methods:
- Accelerated molecular dynamics (aMD) simulations were employed to analyze conformational dynamics.
- Dynamic cross-correlation map (DCCM) and principal component analysis (PCA) assessed kinetic behavior.
- Molecular mechanics generalized Born surface area (MM-GBSA) and free energy decomposition were used to study binding affinity and interactions.
Main Results:
- Inhibitor binding significantly altered PGAM1's kinetic behavior and conformational landscape.
- Compounds 9HU and HKB exhibited enhanced binding to PGAM1 compared to 8KX, attributed to specific chemical modifications.
- Hydrophobic interactions were identified as crucial for inhibitor binding, with key residues like F22, R90, and Y92 highlighted.
Conclusions:
- Developing anthraquinone-based small molecules targeting PGAM1 is a viable strategy for cancer therapy.
- Specific structural modifications, such as sulphonamide reversal and trifluoromethyl substitution, enhance inhibitor potency.
- Key PGAM1 residues identified provide valuable targets for the rational design of novel anticancer drugs.
Related Concept Videos
02:54Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
01:22Amplifying Signals via Enzymatic Cascade
01:18Indirect-Acting Cholinergic Agonists: Mechanism of Action
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
01:30Enzyme Inhibition