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Binding Free Energy Estimation for Protein-Ligand Complex Based on MM-PBSA with Various Partial Charge Models
Fu, Ting1,2,3; Jin, Zhong4; Xiu, Zhilong3; Li, Guohui1
KeywordBinding Free Energy Charge Model Drug Design
Source PublicationCURRENT PHARMACEUTICAL DESIGN
2013-04-01
Volume19Issue:12Pages:2293-2307
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectPharmacology & Pharmacy
WOS Research AreaPharmacology & Pharmacy
WOS KeywordEMPIRICAL SCORING FUNCTION ; MOLECULAR-MECHANICS ; FORCE-FIELD ; CONTINUUM MODELS ; DRUG-RESISTANCE ; ATOMIC CHARGES ; INACTIVE CDK2 ; INHIBITORS ; AFFINITIES ; DYNAMICS
AbstractAn accurate estimation of binding free energy between protein and ligand, is one of the most important issues in the drug discovery process. However, it is an arduous and hard process to obtain accurate energy, especially the experimentally relevant free energies for protein-ligand in solution, including a proper treatment of the long-range electrostatics and solvation effects that are involved in optimization of atomic net charges and so on. In this study, the impacts of the various atomic net charge models were considered, and their effects on binding free energy profiles also were investigated. The methods were tested on: the 30 structurally diverse ligands of diverse protein complexes, the 14 structurally diverse ligands of the protein kinase B (PKB) and the 10 structurally diverse ligands of the cyclin-dependent kinases 2 (CDK2) with measured affinities. The tested charges were calculated based on AM1 (Austin Method, version 1) BCC (bond charge correction), MNDO (modified neglect of diatomic differential overlay), PM5 (Parameterisation Model, version 5), MUL (Mulliken), CM2 (Charge Model 2), CM3 (Charge Model 3), RESP (restrained electrostatic potential) and QM/MM (quantum mechanics/molecular mechanics) models. Our findings showed that the MNDO charge model was best propitious for PKB system and QM/MM for CDK2, whereas none of any given models was suited for the diverse ligands of diverse protein complexes. The trends of MM-PBSA binding free energies using all charge models were in good accord with experimental results for CDK2 but not for PKB in most cases. Considering the above results, particular attention should be paid to the ligand-charge and maybe protein-charge during the estimation of accurate binding free energies in drug design.
Language英语
WOS IDWOS:000316457700016
Citation statistics
Cited Times:7[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/137724
Collection中国科学院大连化学物理研究所
Affiliation1.Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Lab Mol Modeling & Design, Dalian 116023, Peoples R China
2.Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China
3.Dalian Univ Technol, Dept Biosci & Biotechnol, Dalian 116024, Peoples R China
4.Chinese Acad Sci, Comp Network Informat Ctr, Supercomp Ctr, Beijing 100190, Peoples R China
Recommended Citation
GB/T 7714
Fu, Ting,Jin, Zhong,Xiu, Zhilong,et al. Binding Free Energy Estimation for Protein-Ligand Complex Based on MM-PBSA with Various Partial Charge Models[J]. CURRENT PHARMACEUTICAL DESIGN,2013,19(12):2293-2307.
APA Fu, Ting,Jin, Zhong,Xiu, Zhilong,&Li, Guohui.(2013).Binding Free Energy Estimation for Protein-Ligand Complex Based on MM-PBSA with Various Partial Charge Models.CURRENT PHARMACEUTICAL DESIGN,19(12),2293-2307.
MLA Fu, Ting,et al."Binding Free Energy Estimation for Protein-Ligand Complex Based on MM-PBSA with Various Partial Charge Models".CURRENT PHARMACEUTICAL DESIGN 19.12(2013):2293-2307.
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