Optimized hydrophobic interactions and hydrogen bonding at the target-ligand interface leads the pathways of drug-designing

Weak intermolecular interactions such as hydrogen bonding and hydrophobic interactions are key players in stabilizing energetically-favored ligands, in an open conformational environment of protein structures. However, it is still poorly understood how the binding parameters associated with these in...

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Published in:	PloS one Vol. 5; no. 8; p. e12029
Main Authors:	Patil, Rohan, Das, Suranjana, Stanley, Ashley, Yadav, Lumbani, Sudhakar, Akulapalli, Varma, Ashok K
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 16-08-2010 Public Library of Science (PLoS)
Subjects:	Affinity Amino Acid Sequence Amino acids Analysis Binding Bioinformatics Biological activity Biological effects Biologists Biology Bonding Bonding strength Cancer Chemical bonds Collaboration Computational Biology Computational Biology/Macromolecular Structure Analysis Computational Biology/Sequence Motif Analysis Crystallography CSK Tyrosine-Protein Kinase Docking Drug Design Drug interactions Drugs Education Effectiveness Enzymes Functional groups Humans Hydrogen Hydrogen Bonding Hydrogen bonds Hydrogen ion concentration Hydrophobic and Hydrophilic Interactions Hydrophobicity Hypotheses Influenza Interaction parameters Kinases Ligands Models, Molecular Molecular Biology/Bioinformatics Molecular Sequence Data Pharmacology/Drug Development Phosphotransferases Protein folding Protein Structure, Secondary Protein-Tyrosine Kinases - chemistry Protein-Tyrosine Kinases - metabolism Proteins Proto-Oncogene Proteins c-abl - chemistry Proto-Oncogene Proteins c-abl - metabolism Pyrimidines Pyrimidines - chemistry Pyrimidines - metabolism Src protein src-Family Kinases Structure-activity relationships Studies Target recognition Weak interactions (field theory) Mumbai India United States > US Nebraska India
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Summary:	Weak intermolecular interactions such as hydrogen bonding and hydrophobic interactions are key players in stabilizing energetically-favored ligands, in an open conformational environment of protein structures. However, it is still poorly understood how the binding parameters associated with these interactions facilitate a drug-lead to recognize a specific target and improve drugs efficacy. To understand this, comprehensive analysis of hydrophobic interactions, hydrogen bonding and binding affinity have been analyzed at the interface of c-Src and c-Abl kinases and 4-amino substituted 1H-pyrazolo [3, 4-d] pyrimidine compounds. In-silico docking studies were performed, using Discovery Studio software modules LigandFit, CDOCKER and ZDOCK, to investigate the role of ligand binding affinity at the hydrophobic pocket of c-Src and c-Abl kinase. Hydrophobic and hydrogen bonding interactions of docked molecules were compared using LigPlot program. Furthermore, 3D-QSAR and MFA calculations were scrutinized to quantify the role of weak interactions in binding affinity and drug efficacy. The in-silico method has enabled us to reveal that a multi-targeted small molecule binds with low affinity to its respective targets. But its binding affinity can be altered by integrating the conformationally favored functional groups at the active site of the ligand-target interface. Docking studies of 4-amino-substituted molecules at the bioactive cascade of the c-Src and c-Abl have concluded that 3D structural folding at the protein-ligand groove is also a hallmark for molecular recognition of multi-targeted compounds and for predicting their biological activity. The results presented here demonstrate that hydrogen bonding and optimized hydrophobic interactions both stabilize the ligands at the target site, and help alter binding affinity and drug efficacy.
Bibliography:	Conceived and designed the experiments: AKV. Performed the experiments: RP SD A. Stanley. Analyzed the data: RP SD LY A. Sudhakar AKV. Wrote the paper: AKV. Current address: School of Informatics and Computing, Indiana University, Bloomington, Indiana, United States of America
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0012029