Molecular modelling probes: docking and scoring

2003 ◽  
Vol 31 (5) ◽  
pp. 980-984 ◽  
Author(s):  
R.T. Kroemer
Keyword(s):  
Binding Site ◽  
Molecular Modelling ◽  
Statistical Treatment ◽  
General Introduction ◽  
Site Analysis ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Modelling Techniques ◽  
Docking And Scoring

A general introduction to molecular modelling techniques in the area of protein–ligand interactions is given. Methods covered range from binding-site analysis to statistical treatment of sets of ligands. The main focus of this paper is on docking and scoring. After an outline of the main concepts, two specific application examples are given.

Prediction of Protein−Ligand Interactions. Docking and Scoring:  Successes and Gaps

2006 ◽  
Vol 49 (20) ◽  
pp. 5851-5855 ◽  
Author(s):  
Andrew R. Leach ◽  
Brian K. Shoichet ◽  
Catherine E. Peishoff
Keyword(s):  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Docking And Scoring

Molecular Modelling of Protein - Ligand Interactions

2010 ◽  
Vol 101 (7) ◽  
pp. 661-662 ◽  
Author(s):  
P. D. J. Grootenhuis ◽  
V. J. van Geerestein ◽  
C. A. G. Haasnoot ◽  
M. Karplus
Keyword(s):  
Molecular Modelling ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

Correlating structure and ligand affinity in drug discovery: a cautionary tale involving second shell residues

2014 ◽  
Vol 395 (7-8) ◽  
pp. 891-903 ◽  
Author(s):  
Anastasia Tziridis ◽  
Daniel Rauh ◽  
Piotr Neumann ◽  
Petr Kolenko ◽  
Anja Menzel ◽  
...  
Keyword(s):  
Binding Site ◽  
Proteinase Inhibitors ◽  
Factor Xa ◽  
Serine Proteinase ◽  
Crystallographic Structure ◽  
Binding Modes ◽  
Ligand Complex ◽  
Structure Based Drug Design ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

Abstract A high-resolution crystallographic structure determination of a protein–ligand complex is generally accepted as the ‘gold standard’ for structure-based drug design, yet the relationship between structure and affinity is neither obvious nor straightforward. Here we analyze the interactions of a series of serine proteinase inhibitors with trypsin variants onto which the ligand-binding site of factor Xa has been grafted. Despite conservative mutations of only two residues not immediately in contact with ligands (second shell residues), significant differences in the affinity profiles of the variants are observed. Structural analyses demonstrate that these are due to multiple effects, including differences in the structure of the binding site, differences in target flexibility and differences in inhibitor binding modes. The data presented here highlight the myriad competing microscopic processes that contribute to protein–ligand interactions and emphasize the difficulties in predicting affinity from structure.

scholarly journals Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction

2019 ◽  
Author(s):  
Brent W. Anderson ◽  
Kuanqing Liu ◽  
Christine Wolak ◽  
Katarzyna Dubiel ◽  
Kenneth A. Satyshur ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Protein Interactions ◽  
Binding Motif ◽  
Protein Ligand Interactions ◽  
Protein Interfaces ◽  
Ligand Interactions ◽  
Binding Residues ◽  
The Common ◽  
Ligand Regulation

ABSTRACTThe signaling ligand (p)ppGpp binds diverse targets across bacteria, yet the mechanistic and evolutionary basis underlying these ligand-protein interactions remains poorly understood. Here we identify a novel (p)ppGpp binding motif in the enzyme HPRT, where (p)ppGpp shares identical binding residues for PRPP and nucleobase substrates to regulate purine homeostasis. Intriguingly, HPRTs across species share the conserved binding site yet strongly differ in ligand binding, from strong inhibition by basal (p)ppGpp levels to weak regulation at induced concentrations. Surprisingly, strong ligand binding requires an HPRT dimer-dimer interaction that allosterically opens the (p)ppGpp pocket. This dimer-dimer interaction is absent in the common ancestor but evolved to favor (p)ppGpp binding in the vast majority of bacteria. We propose that the evolutionary plasticity of oligomeric interfaces enables allosteric adjustment of ligand regulation, bypassing constraints of the ligand binding site. Since most ligands bind near protein-protein interfaces, this principle likely extends to other protein-ligand interactions.

scholarly journals Molecular basis for high affinity agonist binding in GPCRs

2018 ◽  
Author(s):  
Tony Warne ◽  
Patricia C. Edwards ◽  
Andrew S. Doré ◽  
Andrew G. W. Leslie ◽  
Christopher G. Tate
Keyword(s):  
Hydrogen Bonds ◽  
Binding Site ◽  
G Protein ◽  
Molecular Basis ◽  
Agonist Binding ◽  
High Affinity ◽  
Protein Ligand Interactions ◽  
Wide Range ◽  
Ligand Interactions ◽  
G Protein Coupled

AbstractA characteristic of GPCRs in the G protein-coupled state is that the affinity of the agonist often increases significantly, but the molecular basis for this is unclear. We have determined six active-state structures of the β1-adrenoceptor (β1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. A direct comparison with structures of β1AR in inactive states bound to the identical ligands showed a 24-42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. GPCRs are highly conserved, so these factors will likely be essential in increasing the affinity of a wide range of structurally distinct agonists.One Sentence SummaryHigh affinity agonist binding to G protein-coupled GPCRs results from an increase in the number and strength of protein-ligand interactions.

scholarly journals ABS–Scan: In silico alanine scanning mutagenesis for binding site residues in protein–ligand complex

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 214 ◽  
Author(s):  
Praveen Anand ◽  
Deepesh Nagarajan ◽  
Sumanta Mukherjee ◽  
Nagasuma Chandra
Keyword(s):  
Binding Site ◽  
In Silico ◽  
Ligand Recognition ◽  
Loss Of Function ◽  
Ligand Complex ◽  
Alanine Scanning Mutagenesis ◽  
Ligand Interaction ◽  
Alanine Scanning ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

Most physiological processes in living systems are fundamentally regulated by protein–ligand interactions. Understanding the process of ligand recognition by proteins is a vital activity in molecular biology and biochemistry. It is well known that the residues present at the binding site of the protein form pockets that provide a conducive environment for recognition of specific ligands. In many cases, the boundaries of these sites are not well defined. Here, we provide a web-server to systematically evaluate important residues in the binding site of the protein that contribute towards the ligand recognition through in silico alanine-scanning mutagenesis experiments. Each of the residues present at the binding site is computationally mutated to alanine. The ligand interaction energy is computed for each mutant and the corresponding ΔΔG values are computed by comparing it to the wild type protein, thus evaluating individual residue contributions towards ligand interaction. The server will thus provide clues to researchers about residues to obtain loss-of-function mutations and to understand drug resistant mutations. This web-tool can be freely accessed through the following address: http://proline.biochem.iisc.ernet.in/abscan/.

Prediction of Protein—Ligand Interactions. Docking and Scoring: Successes and Gaps

ChemInform ◽  
2006 ◽  
Vol 37 (50) ◽  
Author(s):  
Andrew R. Leach ◽  
Brian K. Shoichet ◽  
Catherine E. Peishoff
Keyword(s):  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Docking And Scoring

Role of AMPK signaling in Repigmentation- An Insilico study

2019 ◽  
Vol 1 (6) ◽  
pp. 253-257
Author(s):  
Thenmozhi M ◽  
Murugesan A ◽  
Kumaravel S.T
Keyword(s):  
Immune System ◽  
Drug Development ◽  
Binding Site ◽  
Development Process ◽  
Adenosine Monophosphate ◽  
Drug Development Process ◽  
Ampk Signaling ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

Vitiligo is an epidermal disorder causes depigmented patches resulted from the loss of melanocytes, Autoimmunity hypotheses strongly supports that the immune system compartments responsible in the development of vitiligo. Adenosine MonoPhosphate kinase (AMPK) signaling plays a role in regimentation in vitiligo. In this present study, set of ligands selected to dock against AMPK protein in the AMP binding site using FlexX software. Based on the scores and protein-ligand interactions selected ligands were analyzed for its binding affinity and protein ligand stability for its further drug development process.

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