Docking (molecular)

About: Docking (molecular) is a research topic. Over the lifetime, 15375 publications have been published within this topic receiving 307552 citations. The topic is also known as: interaction simulation & molecular docking.

A conserved docking motif in MAP kinases common to substrates, activators and regulators

Abstract: Mitogen-activated protein kinases (MAPKs) are specifically phosphorylated and activated by the MAPK kinases, phosphorylate various targets such as MAPK-activated protein kinases and transcription factors, and are inactivated by specific phosphatases. Recently, docking interactions via the non-catalytic regions of MAPKs have been suggested to be important in regulating these reactions. Here we identify docking sites in MAPKs and in MAPK-interacting enzymes. A docking domain in extracellular-signal-regulated kinase (ERK), a MAPK, serves as a common site for binding to the MAPK kinase MEK1, the MAPK-activated protein kinase MNK1 and the MAPK phosphatase MKP3. Two aspartic acids in this domain are essential for docking, one of which is mutated in the sevenmaker mutant of Drosophila ERK/Rolled. A corresponding domain in the MAPKs p38 and JNK/SAPK also serves as a common docking site for their MEKs, MAPK-activated protein kinases and MKPs. These docking interactions increase the efficiency of the enzymatic reactions. These findings reveal a hitherto unidentified docking motif in MAPKs that is used in common for recognition of their activators, substrates and regulators.

Insights into Protein-Ligand Interactions: Mechanisms, Models, and Methods

Abstract: Molecular recognition, which is the process of biological macromolecules interacting with each other or various small molecules with a high specificity and affinity to form a specific complex, constitutes the basis of all processes in living organisms. Proteins, an important class of biological macromolecules, realize their functions through binding to themselves or other molecules. A detailed understanding of the protein–ligand interactions is therefore central to understanding biology at the molecular level. Moreover, knowledge of the mechanisms responsible for the protein-ligand recognition and binding will also facilitate the discovery, design, and development of drugs. In the present review, first, the physicochemical mechanisms underlying protein–ligand binding, including the binding kinetics, thermodynamic concepts and relationships, and binding driving forces, are introduced and rationalized. Next, three currently existing protein-ligand binding models—the “lock-and-key”, “induced fit”, and “conformational selection”—are described and their underlying thermodynamic mechanisms are discussed. Finally, the methods available for investigating protein–ligand binding affinity, including experimental and theoretical/computational approaches, are introduced, and their advantages, disadvantages, and challenges are discussed.

Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1.

Abstract: The three‐dimensional structure of stromal cell‐derived factor‐1 (SDF‐1) was determined by NMR spectroscopy. SDF‐1 is a monomer with a disordered N‐terminal region (residues 1–8), and differs from other chemokines in the packing of the hydrophobic core and surface charge distribution. Results with analogs showed that the N‐terminal eight residues formed an important receptor binding site; however, only Lys‐1 and Pro‐2 were directly involved in receptor activation. Modification to Lys‐1 and/or Pro‐2 resulted in loss of activity, but generated potent SDF‐1 antagonists. Residues 12–17 of the loop region, which we term the RFFESH motif, unlike the N‐terminal region, were well defined in the SDF‐1 structure. The RFFESH formed a receptor binding site, which we propose to be an important initial docking site of SDF‐1 with its receptor. The ability of the SDF‐1 analogs to block HIV‐1 entry via CXCR4, which is a HIV‐1 coreceptor for the virus in addition to being the receptor for SDF‐1, correlated with their affinity for CXCR4. Activation of the receptor is not required for HIV‐1 inhibition.

Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations.

Abstract: Three different database docking programs (Dock, FlexX, Gold) have been used in combination with seven scoring functions (Chemscore, Dock, FlexX, Fresno, Gold, Pmf, Score) to assess the accuracy of virtual screening methods against two protein targets (thymidine kinase, estrogen receptor) of known three-dimensional structure. For both targets, it was generally possible to discriminate about 7 out of 10 true hits from a random database of 990 ligands. The use of consensus lists common to two or three scoring functions clearly enhances hit rates among the top 5% scorers from 10% (single scoring) to 25−40% (double scoring) and up to 65−70% (triple scoring). However, in all tested cases, no clear relationships could be found between docking and ranking accuracies. Moreover, predicting the absolute binding free energy of true hits was not possible whatever docking accuracy was achieved and scoring function used. As the best docking/consensus scoring combination varies with the selected target and the physicoch...