Ligands macromolecules

The principle of specific chemical recognition is common to ligand—macromolecule interactions, but this alone does not suffice to define a receptor in the pharmacologic sense. Rather, it is the combination of chemical specificity or recognition and the capacity to initiate biological response or transduction that define the pharmacologic receptor (1,10,11). 

Gresh N, Cisneros GA, Darden TA, Piquemal J-P (2007) Anisotropic, polarizable molecular mechanics studies of inter-, intra-molecular interactions, and ligand-macromolecule complexes. A bottom-up strategy. J Chem Theory Comput 3 1960... 

CV Thomas, AC Cater, JJ Wheeler. HPCE as an analytical probe for assessing irreversible ligand/macromolecule binding interactions. J Liq Chromatogr 16 1903-1921, 1993. 

When visualizing ligand-macromolecule interactions, we differentiate between the ligand core molecule) and its immediate environment. The environment consists of all atoms in the macromolecule residing within a distance of up to 5 A from the ligand. 

Table 1. Information on ligands, macromolecules and their complexes sought in structure-based design and relevant NMR technologies used to derive this information...

Ligand- macromolecule complex Stoichiometry of complex Kinetics of binding Location of interacting sites Orientation of bound ligand Structure of complex Dynamics of complex Chemical shift titration Line width, titration analysis HSQC, isotope editing NOE docking 3D/4D NMR Relaxation time measurements... 

From the preceding discussion it can be seen that NMR can provide a vast range of information on ligands, macromolecules and their complexes. However, within the pharmaceutical industry the value of a particular piece of information must be assessed against the cost of obtaining it. As might be... 

Murray-Rust, P. and Glusker, J. P., Directional hydrogen bonding to sp - and. sp -hybridizedoxygen atoms and its relevance to ligand-macromolecule interactions, J. Am. Chem. Soc. 106, 1018-1025 (1984). 

Tel. 619-566-1127, fax 619-586-1481, e-mail haney netcom.com Hydropathic INTeraction by empirical calculation of atomistic hydrophobicity of molecules. Grid points based on energetics of hydrophobic and hydrophilic fields can be used for contouring a hydrophobic space and for scoring ligand-macromolecule and macromolecule-macromolecule interactions. Interfaced to SYBYL (CoMFA), Insight II, and Chem-X. Silicon Graphics and Evans 8c Sutherland ESV workstations. 

TaMe 12.3 Information on Ligands, Macromolecules, and Their Complexes Sought in Structure-Based Design and Relevant NMR Technologies Used to Derive This Information... 

Distance Geometry Approach to Ligand-Macromolecule Docking. ... 

Local or global molecular descriptors related to the electronic distribution in the molecule they are fundamental to many chemical reactions, physico-chemical properties, and ligand-macromolecule interactions. The theory of electronic density is based on a quantum-mechanical approach however, - electronegativity and charges, which are not physical observables, are also important quantities for the definition of several electronic descriptors. 

Verkhivker, G. M., D. Bouzida, D. K. Gehlhaar, P. A. Rejto, S. T. Freer, and P. W. Rose. 2002. Complexity and simplicity of ligand-macromolecule interactions The energy landscape perspective. Curr Opin Struct Biol 12 197-203. 

The X-ray crystallographic sturcture of the specific macromolecular receptor is the best starting point for designing a ligand for it. Over 300 X-ray crystal structures of proteins and nucleic acids have now been solved, including several ligand-macromolecule complexes (55) most of these are available in the Brookhaven Protein Data Bank (14). NMR is also now providing the equivalent of medium ( 3 A) resolution structures for proteins up to about 100 residues (15-17, 56). 

Fortunately, once a parent macromolecular structure has been solved, new structures of the macromolecule complexed with different ligands can often be solved very quickly (within a few days in some cases (57)). These new structures are determined by cocrystallization of the ligand-macromolecule complex or by soaking protein crystals in a solution of the ligand and allowing the ligand to diffuse into the binding site. 

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