{"title":"Accelerated molecular dynamics study of interaction mechanism between small molecule inhibitors and phosphoglycerate mutantase 1","authors":"Yanqi Sun, Chaoyue Jia, Shaolong Zhang, Qinggang Zhang, Jianzhong Chen, Xinguo Liu","doi":"10.1039/d4cp03309d","DOIUrl":null,"url":null,"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 calculation 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.","PeriodicalId":99,"journal":{"name":"Physical Chemistry Chemical Physics","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Physical Chemistry Chemical Physics","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1039/d4cp03309d","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
引用次数: 0
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 calculation 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.
期刊介绍:
Physical Chemistry Chemical Physics (PCCP) is an international journal co-owned by 19 physical chemistry and physics societies from around the world. This journal publishes original, cutting-edge research in physical chemistry, chemical physics and biophysical chemistry. To be suitable for publication in PCCP, articles must include significant innovation and/or insight into physical chemistry; this is the most important criterion that reviewers and Editors will judge against when evaluating submissions.
The journal has a broad scope and welcomes contributions spanning experiment, theory, computation and data science. Topical coverage includes spectroscopy, dynamics, kinetics, statistical mechanics, thermodynamics, electrochemistry, catalysis, surface science, quantum mechanics, quantum computing and machine learning. Interdisciplinary research areas such as polymers and soft matter, materials, nanoscience, energy, surfaces/interfaces, and biophysical chemistry are welcomed if they demonstrate significant innovation and/or insight into physical chemistry. Joined experimental/theoretical studies are particularly appreciated when complementary and based on up-to-date approaches.