Complexes protein-ligand

Bdhm H-J 1994 The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure J. Comp.-Aided Mol. Design 8 243-56... 

That simulation study [49] aimed at a microscopic interpretation of single molecule atomic force microscope (AFM) experiments [50], in which unbinding forces between individual protein-ligand complexes have been m( asured... 

To enable an atomic interpretation of the AFM experiments, we have developed a molecular dynamics technique to simulate these experiments [49], Prom such force simulations rupture models at atomic resolution were derived and checked by comparisons of the computed rupture forces with the experimental ones. In order to facilitate such checks, the simulations have been set up to resemble the AFM experiment in as many details as possible (Fig. 4, bottom) the protein-ligand complex was simulated in atomic detail starting from the crystal structure, water solvent was included within the simulation system to account for solvation effects, the protein was held in place by keeping its center of mass fixed (so that internal motions were not hindered), the cantilever was simulated by use of a harmonic spring potential and, finally, the simulated cantilever was connected to the particular atom of the ligand, to which in the AFM experiment the linker molecule was connected. 

Equilibria in Solution The stability of a protein-ligand complex in solution is measured in terms of the equilibrium constant and the standard free energy of association based on it. For association of species P and L in solution to form a complex PL, i.e., for... 

Bonaccorsi ct al. [204 defined for the first time the molecular electrostatic potential (MEP), wdicli is dearly tfie most important and most used property (Figure 2-125c. The clcctro.static potential helps to identify molecular regions that arc significant for the reactivity of compounds. Furthermore, the MEP is decisive for the formation of protein-ligand complexes. Detailed information is given in Ref [205]. 

R E and S L Bender 1997. Recognition of Protein-Ligand Complexes Applications to Drug sign. Chemical Reviews 97 1359-1472. 

I-J 1994. The Development of a Simple Empirical Scoring Fimction to Estimate the Binding istant for a Protein-ligand Complex of Known Three-Dimensional Structure. Journal of nputer-Aided Molecular Design 8 243-256. 

Molecular recognition of protein-ligand complexes and drug design 97CRV1369. 

Isomorphous replacement is where the phases from a previous sample are used directly for a protein that has crystallized in exactly the same space group as before. This is usually applicable to determining the structure of many protein-ligand complexes or protein mutants. 

For many proteins, it is possible to generate structures of protein-ligand complexes quite rapidly. It is therefore not uncommon for many hundreds of structures to be determined in support of a drug discovery and optimization project. The major challenge for this level of throughput is informatics support. It is also this type of crystallography that is most in need of semiautomated procedures for structure solution and model building (see Section 12.6). 

A database of lattice protein-ligand complexes is now constructed with the following steps ... 

It is important to emphasize that this lattice database is highly idealized compared to real databases. Unlike the lattice database, real databases cannot be treated as thermodynamic ensembles of protein-ligand complexes equilibrated at room temperature [33,34]. Two of the more straightforward reasons are mentioned here. First, real databases are inherently biased toward strong binders (K < 10 pM), because weak binders are difficult to crystallize and of lesser interest. Second, as mentioned above, real databases are not composed of a representative selection of proteins and ligands, and their compositions are biased toward peptide and peptidomimetic inhibitors and certain protein superfamilies. In contrast, because only one protein and four ligand types are used, the lattice database should have representative ligand compositions. 

Raha K, Merz KM. Large-scale validation of a quantum mechanics based scoring function predicting the binding affinity and the binding mode of a diverse set of protein-ligand complexes. J Med Chem 2005 48 4558-75. 

Wang R, Fang X, Lu Y, Wang S. The PDBbind database collection of binding affinities for protein-ligand complexes with known three-dimensional structures. JMed Chem 2004 47 2977-80. 

Roche O, Kiyama R, Brooks CL 3rd. Ligand-protein database linking protein-ligand complex strnctnres to binding data. J Med Chem 2001 44 3592-8. 

CombiSMoG potential function, which was derived from 1000 protein-ligand complex 3D structures. After inspection of 100,000 candidates, the hve best hits were ranked by a force field calculation. The (i )-isomer of the indole compound 59 (K = 30 pM Fig. 16.8) is the highest-scoring compound and has the highest affinity of all synthesized molecules, whereas the (S) -isomer has only K = 230 pM [131,132]. 

Bohm HI, Klebe G. What can we learn from molecular recognition in protein-ligand complexes for the design of new drugs Angew Chem Int Ed Engl 1996 35 2589-614. 

Babine RE, Bender SL. Molecular recognition of protein-ligand complexes applications to drug design. Chem Rev 1997 97 1359-472. 

The abundance of structural information has led to a significant increase in the use of structure-based methods both to identify and to optimise inhibitors of protein kinases. The focus to date has centred upon small molecule ATP-competitive inhibitors and there are numerous examples of protein-ligand complexes available to guide design strategies. ATP binds in the cleft formed between the N- and C-terminal lobes of the protein kinase, forming several key interactions conserved across the protein kinase family. The adenine moiety lies in a hydrophobic region between the jS-sheet structure of subdomains I and II and residues from subdomains V and VIb. A... 

Despite the major advances in X-ray crystallography, the process of producing multiple protein-ligand complexes is not able to handle anywhere... 

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