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Related Concept Videos

Ligand Binding Sites02:40

Ligand Binding Sites

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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
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The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
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The hemoglobin in the blood, the chlorophyll in green plants, vitamin B-12, and the catalyst used in the manufacture of polyethylene all contain coordination compounds. Ions of the metals, especially the transition metals, are likely to form complexes.
In these complexes, transition metals form coordinate covalent bonds, a kind of Lewis acid-base interaction in which both of the electrons in the bond are contributed by a donor (Lewis base) to an electron acceptor (Lewis acid). The Lewis acid in...
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Different monodentate and polydentate ligands are used as complexing agents in complexometric titration reactions. The formation of complexes by mono- and bidentate ligands involves two or more intermediate steps, limiting their use as complexing agents. In comparison, polydentate ligands can form complexes with metal ions in a single-step process, facilitating sharper end points. This means polydentate ligands, such as amino carboxylic acid derivatives, are most commonly employed in...
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Crystal Field Theory
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CFT focuses on...
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Sensitivity Analysis and Charge-Optimization for Flexible Ligands:  Applicability to Lead Optimization.

Michael K Gilson1

  • 1Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, Maryland 20850.

Journal of Chemical Theory and Computation
|December 3, 2015
PubMed
Summary
This summary is machine-generated.

Sensitivity analysis and charge-optimization are useful for drug discovery lead optimization. Considering ligand flexibility improves accuracy, with charge optimization showing robust affinity improvements even with conformational changes.

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Area of Science:

  • Computational chemistry
  • Drug discovery
  • Molecular modeling

Background:

  • Sensitivity analysis and charge-optimization guide lead compound optimization in early-stage drug discovery.
  • Previous applications assumed rigid ligands, limiting broader applicability.

Purpose of the Study:

  • To apply sensitivity analysis and charge-optimization to flexible ligands in drug discovery.
  • To evaluate the effectiveness of these methods for optimizing HIV-protease inhibitors.

Main Methods:

  • Formalisms of sensitivity analysis and charge-optimization were applied to a flexible ligand model.
  • A model application involved an HIV-protease inhibitor.

Main Results:

  • Sensitivity analysis proved a fast, robust method for guiding charge changes in both rigid and flexible ligands.
  • Charge-optimization with flexible ligands yielded unexpected results, stabilizing bound conformations.
  • Optimizing charges assuming no conformational change robustly improved affinity, regardless of free state conformation.

Conclusions:

  • Both sensitivity analysis and charge-optimization are valuable techniques for drug discovery.
  • Accounting for ligand flexibility is crucial for accurate charge-optimization results.
  • Charge optimization under rigid assumptions can still yield beneficial results for flexible systems.