Reviews in Computational Chemistry Volume 18

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100 80 60 40 20 Application of Scoring Functions in Virtual Screening 67 COX-2 0 1 2 3 4 5 10 20 30 50 100 FlexX score PLP ScreenScore 0 1 2 3 4 5 10 20 30 50 100 scoring function by including directed hydrogen bonding terms, 63 which may lead to a similarly robust scoring function as ScreenScore. Another example where the balance between H-bonding and hydrophobic contributions is important involves the performance of the knowledgebased scoring function DrugScore. 92 The estrogen receptor binding site is a large lipophilic cavity with acceptor groups at either end that can form hydrogen bonds with ligand hydroxyl groups as present in the agonists 1 and 2 or the antagonists 3 and 4 (Figure 6). The narrow binding pocket and relatively rigid nature of the ligands restrains possible binding modes significantly. Accordingly, it can be assumed that FlexX is capable of generating reasonable solutions likely to be in agreement with experiment. Therefore we can expect the present example to represent a valuable test for scoring functions. For both agonists and antagonists, lipophilic interactions largely determine the binding energy. The majority of antagonists, however, differ from the agonists in an additional side chain bearing a tertiary amino group. This difference is reflected in the bound structures of the receptor. In the agonist-bound state the binding pocket is not accessible to solvent, whereas in the antagonistbound state it opens up and allows the positively charged antagonist side chain to form a salt bridge with the carboxylate group of Glu 351. Agonists should bind equally well to both forms of the receptor. A 7500 compound subset from the World Drug Index (WDI) and a library of 20 agonists and 16 antagonists were docked into both agonist (PDB code 1ere) and antagonist (PDB code 1err) forms of the receptor. FlexX scores obtained from both structures are plotted against each other in Figure 6(a). Due to the large contribution of 100 80 60 40 20 Neuraminidase Figure 5 Results of seeding experiments on two targets with three different scoring functions. In both graphs, the accumulated percentages of active compounds are plotted against the percentage of the total ranked library. The smooth exponential curve in each graph corresponds to the hypothetical case of no enrichment and assumes a random ordering of the database.
68 The Use of Scoring Functions in Drug Discovery Applications Figure 6 Docking estrogen receptor agonists and antagonists into two crystal structures of the estrogen receptor, the agonist-bound conformation and the antagonist-bound conformation. Scores for both docking results are plotted against each other. Compounds 1 and 2 are examples of agonists, compounds 3 and 4 are typical antagonists. the surface-exposed salt bridge formed with Glu 351 to the total score the antagonists are clearly separated from the WDI compounds, whereas the agonists are ranked among the bulk of the WDI entries in the antagonist structure. In the agonist form, the formation of a salt bridge is not possible, resulting in a lower average score for all molecules. Almost the same result as with the FlexX score is obtained with the ChemScore function 71,199 by Protherics. 201 The new DrugScore function 92 performs better in this situation. Using this scoring function, results shown in Figure 6(b) are obtained. Not only are the agonists significantly better separated from the WDI subset
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Reviews in Computational Chemistry
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Kenny B. Lipkowitz Department of Ch
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vi Preface three-dimensional struct
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viii Preface some descriptors and i
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Epilogue and Dedication My associat
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Contents 1. Clustering Methods and
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Contents xv Electron Transfer in Po
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Contributors John M. Barnard, Barna
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Contributors to Previous Volumes *
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Volume 3 (1992) Tamar Schlick, Opti
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Volume 7 (1996) Geoffrey M. Downs a
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Volume 11 (1997) Mark A. Murcko, Re
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T. Daniel Crawford* and Henry F. Sc
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Topics Covered in Volumes 1-18 * Ab
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Reviews in Computational Chemistry
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2 Clustering Methods and Their Uses
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10 Clustering Methods and Their Use
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Page 45 and 46: 16 Clustering Methods and Their Use
Page 71 and 72: 42 The Use of Scoring Functions in
Page 79 and 80: Table 1 Reference List for the Most
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Page 117 and 118: CHAPTER 3 Potentials and Algorithms
Page 119 and 120: Vn (1 + cos(nω + γ)) 2 K θ (θ
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Page 123 and 124: Table 1 Polarizability Parameters f
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Page 131 and 132: Shell Models 103 on estimates of sh
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Page 139 and 140: where we have used q Cl ¼ qNa. The
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is treated using variable charges.
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water have been developed, includin
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Applications 123 classical and rigi
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developing polarizable models. A va
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Comparison of the Polarization Mode
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negligible errors in such propertie
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ecome significant at field strength
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noteworthy in this regard because t
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References 135 9. P. Cieplak and P.
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References 137 48. E. L. Pollock an
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References 139 Computational Chemis
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References 141 139. J. Hinze and H.
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References 143 178. J. J. P. Stewar
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References 145 216. M. W. Mahoney a
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CHAPTER 4 New Developments in the T
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Introduction 149 applications). For
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FCWD(∆E ) FCWD(0) ∆E = 0 ∆E
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Introduction 153 Equations [6]-[12]
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Paradigm of Free Energy Surfaces 15
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Paradigm of Free Energy Surfaces 15
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In Eqs. [18] and [19], F0i is the e
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where ‘‘þ’’ and ‘‘ ’
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is, however, small for the usual co
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solute-solvent coupling through the
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where Z is the electrode overpotent
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energy surfaces of ET. 33,50-56 It
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This result indicates a fundamental
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βF i (X ) 40 20 0 −20 1 2 βλ 1
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Table 1 Main Features of the Two-Pa
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and Hss ¼ U rep ss 1 2 X j;k ðmj
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λ i /eV 4 3 2 1 0 0 10 20 30 40 Bo
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the width/Stokes shift relation (Eq
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Table 3 Mapping of the Q Model on S
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This situation is of course not sat
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F ± (Y ad )/λ I 0.8 0.4 0 −0.4
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it by choosing the GMH basis set 7
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Anharmonic higher order terms gain
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of the radiation is the perturbatio
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individual vibrational excitations
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m 12 /D 6 5.5 5 4.5 4 3.5 17 18 19
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In Eq. [144], the coordinates Y km
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ε/M −1 cm −1 4000 2000 0 analy
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βσ 2 /10 3 cm −1 14 12 10 8 Opt
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0.2 0.1 0 12 16 20 24 28 32 The app
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References 207 7. M. D. Newton, Adv
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References 209 59. R. Kubo and Y. T
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Reviews in Computational Chemistry Volume 18

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