Christian Lemmen HYDE: Scoring for Lead Optimization

Transcription

1 Christian Lemmen HYDE: Scoring for Lead ptimization

2 HYDE = HYdrogen bonding and DEsolvation Virtually every scoring function favors hydrogen bonds. However: Martin Stahl: a primary question in molecular design should be which donors and acceptors need to be satisfied and not how more hydrogen bonds can be formed. * HYDE describes consistently: hydrogen bonds, the hydrophobic effect and desolvation * A medicinal chemist s guide to molecular interactions, JMedChem, 2010 PDB: 1L7F 1

3 The Basic Concept G interaction G desolvation ΔG ΔG ΔG binding atom i i desolvation i interaction * Reulecke et al., ChemMedChem,

4 Atom-Based Desolvation ΔG 2.3RT acc acc plogp i i i desolvation free bound i acc i conformation dependent SAS of atom i plogp i atom based logp contribution i i 3

5 Atom-Based Interaction 2.3RT ΔG sat sat plogp i i i interaction bound free f sat i sat i number of interactions (degree of saturation) f sat reference state (saturation of H bonds in solvent water) i plogp i atom based logp contribution 310K f sat = K f sat = 1 i 4

6 Atom-Based logp Contribution Calibration dataset: 458 small, simple molecules taken from the Starlist * 21 plogp descriptors used plogp(sp2 oxygen) = 1.42 G desolvation = 8.09 kj/mol plogp(aromatic carbon) = 0.45 G desolvation = 1.37 kj/mol * Hansch C. et al., American Chemical Society,

7 Input/utput - Reality Check Experimental logps of small molecules plogp increments f sat HYDE Correct prediction of: hydrophobic effect (110 J/Å 2 ) H bonds in vacuum ( 16 kj/mol) H bonds in water ( 2 to 6 kj/mol) affinity loss of unsatisfied H bond (6 kj/mol) Score reflects affinity of inhibitor to protein G = RT ln(k) 6

8 Binding Mode Analysis with HYDE HYDE color code: + G contribution G contribution no G contribution receptor carbonyl oxygen 8.2 kj/mol ligand aromatic oxygen 2.4 kj/mol desolvation cost kj/mol receptor aromatic carbons 1.7 kj/mol C 8 ligand aromatic carbon hydrophobic effect 1.9 kj/mol 3.6 kj/mol H 7 C6 receptor amide nitrogen 6.3 kj/mol 7.4 kj/mol G experimental 28 kj/mol G HYDE 22 kj/mol ligand aromatic nitrogen 6.4 kj/mol 7.5 kj/mol 2BRB * hydrogen bond energy 2.2 kj/mol * Foloppe. et al., JMedChem

9 HYDE: Guiding ptimization Structure based design of novel Checkpoint kinase 1 inhibitors: Insights into hydrogen bonding and protein ligand affinity * * [Foloppe. et al., JMedChem 2005] 2BRM 2BRB H H H H H G exp G Hyde = -34 kj/mol = -33 kj/mol G exp G Hyde = -28 kj/mol = -22 kj/mol 8

10 HYDE Requires Perfection Stage 2: 1: Crystal structure hydrogen avoid clashes, bond optimize network hydrogen bond optimization geometries * 1X8X G opt = LJpot inter + LJpot intraligand + Torsion Ligand + 2 G HYDEinteract + G HYDEdesolv G HYDE 7 29 kj/mol * Lippert et al., J.Cheminformatics,

11 HYDE Requires Perfection Stage 2: 1: Crystal structure hydrogen avoid clashes, bond optimize network hydrogen bond optimization geometries * 1X8X G opt = LJpot inter + LJpot intraligand + Torsion Ligand + 2 G HYDEinteract + G HYDEdesolv G HYDE kj/mol * Lippert et al., J.Cheminformatics,

12 HYDE Ranking Power * PDBbind Coreset 2007: 195 high resolution complexes and measured K i HYDE ranks 29 of the 65 cases in the right order Sucuess rate: 45 % * Cheng T et al., JChemInfMod,

13 Xtal Assessment an Astex Example 1TT1 glutamate receptor 6 Kainate G experimental G HYDE 43 kj/mol 26 kj/mol 8 excellent H bonds 12

14 Astex Diverse Hyde Results Improved Docking RMS 0.5Å 1.0Å 1.5Å 2.0Å 2.5Å rank % 46.7% 62.7% 74.7% 80.7% rank % 80.7% 88.0% 90.7% 96.0% rank any 57.3% 84.7% 92.0% 95.3% 97.3% 13

15 Hyde Results Improved Screening DUD * FlexX/HYDE * Cross et al., JCIM, 2009, 49, 1455ff 14

16 HYDE Affinity Assessment * Regan et al., JMedChem, 2002 Pyrazole Urea Based Inhibitors of p38 MAP Kinase: From Lead Compound to Clinical Candidate * Cl 15

17 HYDE Affinity Assessment 16

18 HYDE Affinity Assessment 17

19 HYDE Affinity Assessment 18

20 HYDE Affinity Assessment Cl 19

21 HYDE Affinity Assessment 20

22 HYDE Affinity Assessment 21

23 HYDE Affinity Assessment 22

24 HYDE Affinity Assessment 23

25 HYDE Affinity Assessment Cl 24

26 Detailed Affinity Assessment More than a Simple Lipophilic Contact: A Detailed Thermodynamic Analysis of onbasic Residues in the S1 Pocket of Thrombin * D Phe Pro S1 occupant H 2 H R1 2ZDV 2ZDA 2ZF0 2ZC9 2ZFF * Baum et al., JMB,

27 HYDE Analysis of Thrombin Inhibitors 2ZFF 2ZDV H 2 H R ZF ZC G experimental G HYDE D-Phe + Pro S1 occupant 2ZDA 26

28 Conclusions HYDE... is an intuitive and untrained scoring function scores single atom exchanges correctly provides a guideline for lead optimization 27

29 Hyde Contributors Gudrun Lange Robert Klein adine Schneider Matthias Rarey Hans Briem Kristin Engels Thank you Sally Hindle Holger Claußen Marcus Gastreich foryourattention 28

30 HYDE in LeadIT v2.0 Workshop: starting 4pm in room 211 B 29