Computational drug design accommodating receptor flexibility: the relaxed complex scheme.
A novel computational methodology for drug design that accommodates receptor flexibility is described. This "relaxed-complex" method recognizes that ligand may bind to conformations that occur only rarely in the dynamics of the receptor. We have shown that the ligand-enzyme binding modes are very sensitive to the enzyme conformations, and our approach is capable of finding the best ligand-enzyme complexes. This new method serves as the computational analog of the experimental "SAR by NMR" and "tether" methods, which permit a building block approach for constructing a very potent drug.
Lin
Jung-Hsin
JH
Howard Hughes Medical Institute, Department of Chemistry & Biochemistry, and Department of Pharmacology, University of California at San Diego, 92093-0365, USA. jlin@maccammon.ucsd.edu
Perryman
Alexander L
AL
Schames
Julie R
JR
McCammon
J Andrew
JA
D000465:Algorithms; D003198:Computer Simulation; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D011955:Receptors, Drug / Q000737:chemistry*; D022021:Tacrolimus Binding Proteins / Q000737:chemistry; D013816:Thermodynamics
D008024:Ligands; D011955:Receptors, Drug; D022021:Tacrolimus Binding Proteins