The ability to propose reasonable ligand-receptor binding geometries is crucial to the success of structure-based drug design. One approach is to “dock” molecules together in many ways and then “score” or evaluate each orientation; in a database of compounds, those which score well should be more likely to bind to the target macromolecule. A method that combines a rapid, geometric docking algorithm with the evaluation of molecular mechanics interaction energies is presented. The “force field score” is successful in identifying the experimental binding mode in four systems, and represents an improvement over the other scoring methods tested. The degree of orientational sampling required to reproduce and identify the known geometries, with and without energy-minimization, is also investigated. Both scoring and sampling issues are of paramount importance to the usefulness of molecular docking in real-life applications.
GoodfordPJA Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules. J Med Chem. 1985;28(7):849–857.
13.
WeinerSJKollmanPACaseDASinghUCGhioCAlagonaGProfetaSJrWeinerPA New Force Field for Molecular Mechanical Simulation of Nucleic Acids and Proteins. J Am Chem Soc. 1984;106(3):765–784.
14.
WeinerSJKollmanPANguyenDTCaseDAAn All Atom Force Field for Simulations of Proteins and Nucleic Acids. J Comp Chem. 1986;7(2):230–252.
15.
DesJarlaisRLSheridanRPSeibelGLDixonJSKuntzIDVenkataraghavanRUsing Shape Complementarity as an Initial Screen in Designing Ligands for a Receptor Binding Site of Known Three-Dimensional Structure. J Med Chem. 1988;31(4):722–729.
16.
ShoichetBKKuntzIDProtein Docking and Complementarity. J Mol Biol. 1991;221(1):327–346.
17.
ShoichetBKBodianDLKuntzIDMolecular Docking Using Shape Descriptors. J Comp Chem. 1992;13(3):380–397.
18.
ConnollyMLSolvent-Accessible Surfaces of Proteins and Nucleic Acids. Science. 1983;221(4612):709–713.
19.
FerroDRHermansJA Different Best Rigid-Body Molecular Fit Routine. Acta Crystallogr. 1977;A33(2):345–347.
20.
KlapperIHagstromRFineRSharpKHonigBFocusing of Electric Fields in the Active Site of Cu-Zn Superoxide Dismutase: Effects of Ionic Strength and Amino-Acid Modification. Proteins. 1986;1(1):47–59.
21.
GilsonMKSharpKAHonigBHCalculating the Electrostatic Potential of Molecules in Solution: Method and Error Assessment. J Comp Chem. 1987;9(4):327–335.
22.
HaglerATHulerELifsonSEnergy Functions for Peptides and Proteins. I. Derivation of a Consistent Force Field Including the Hydrogen Bond from Amide Crystals. J Am Chem Soc. 1977;96(17):5319–5335.
23.
BernsteinFCKoetzleTFWilliamsGJBMeyerEFJrBriceMDRodgersJRKennardOShimanouchiTTasumiMThe Protein Data Bank: A Computer-Based Archival File for Macromolecular Structures. J Mol Biol. 1977;112(3):535–542.
BolinJTFilmanDJMatthewsDAHamlinRCKrautJCrystal Structures of Escherichia coli and Lactobacillus casei Dihydrofolate Reductase Refined at 1.7 Angstroms Resolution. I. General Features and Binding of Methotrexate. J Biol Chem. 1982;257(22):13650–13662.
26.
BorahBChenC-WEganWMillerMWlodawerACohenJSNuclear Magnetic Resonance and Neutron Diffraction Studies of the Complex of Ribonuclease A with Uridine Vanadate, a Transition-State Analogue. Biochemistry. 1985;24(8):2058–2067.
27.
VyasNKVyasMNQuiochoFASugar and Signal-Transducer Binding Sites of the Escherichia coli Galactose Chemoreceptor Protein. Science. 1988;242(4883): 1290–1295.
28.
BlaneyJM Ph.D. dissertation, University of California, San Francisco, 1982.
29.
SinghUCKollmanPAAn Approach to Computing Electrostatic Charges for Molecules. J Comp Chem. 1984;5(2):129–145.
30.
GasteigerJMarsiliMIterative Partial Equalization of Orbital Electronegativity — A Rapid Access to Atomic Charges. Tetrahedron. 1980;36(22):3219–3228.
31.
StreitweiserA.Molecular Orbital Theory for Organic Chemists. New York: Wiley; 1961.
32.
Molecular Modeling System SYBYL, Version 5.4, TRIPOS Associates, Inc., St. Louis, MO 63117.
33.
GilsonMKHonigBCalculation of the Total Electrostatic Energy of a Macromolecular System: Solvation Energies, Binding Energies, and Conformational Analysis. Proteins. 1988;4(1):7–18.
34.
DavisMEMcCammonJACalculating Electrostatic Forces from Grid-Calculated Potentials. J Comp Chem. 1990;11(3):401–409.
35.
DesJarlaisRLSheridanRPDixonJSKuntzIDVenkataraghavanRDocking Flexible Ligands to Macromolecular Receptors by Molecular Shape. J Med Chem. 1986;29(11):2149–2153.
36.
LeachARKuntzIDConformational Analysis of Flexible Ligands in Macromolecular Receptor Sites. J Comp Chem. 1992;13(6):730–748.
37.
EisenbergDMcLachlanADSolvation Energy in Protein Folding and Binding. Nature. 1986;319(6050):199–203.
38.
ChicheLGregoretLMCohenFEKollmanPAProtein Model Structure Evaluation Using the Solvation Free Energy of Folding. Proc Natl Acad Sci USA. 1990;87(8):3240–3243.
