Computational methods used in hit-to-lead and lead optimization stages of structure-based drug discovery

Methods in Molecular Biology

Volumn 1705, Issue , 2018, Pages 375-394

  Heifetz, Alexander ^a,b   Southey, Michelle ^a   Morao, Inaki ^a   Townsend Nicholson, Andrea ^b   Bodkin, Mike J ^a  

^a EVOTEC UK LTD   (United Kingdom)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

Docking; G protein coupled receptor; Hit to lead; Lead optimization; Molecular dynamics; Simulation; Structure based drug design

Indexed keywords

G PROTEIN COUPLED RECEPTOR; LIGAND; PROTEIN BINDING; WATER;

DRUG DEVELOPMENT; DRUG STRUCTURE; HIT TO LEAD; LEAD OPTIMIZATION; MOLECULAR DYNAMICS; RECEPTOR BINDING ASSAY; BIOLOGY; CHEMISTRY; COMPUTER SIMULATION; METABOLISM; MOLECULAR DOCKING; MOLECULAR MODEL; PROCEDURES; QUANTITATIVE STRUCTURE ACTIVITY RELATION; SOFTWARE; WORKFLOW;

COMPUTATIONAL BIOLOGY; COMPUTER SIMULATION; DRUG DISCOVERY; LIGANDS; MODELS, MOLECULAR; MOLECULAR DOCKING SIMULATION; MOLECULAR DYNAMICS SIMULATION; PROTEIN BINDING; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RECEPTORS, G-PROTEIN-COUPLED; SOFTWARE; WATER; WORKFLOW;

EID: 85036612992     PISSN: 10643745     EISSN: None     Source Type: Book Series    
DOI: 10.1007/978-1-4939-7465-8_19     Document Type: Chapter

References (66)

1. Heifetz A, Schertler GF, Seifert R, Tate CG, Sexton PM, Gurevich VV, Fourmy D, Cherezov V, Marshall FH, Storer RI, Moraes I, Tikhonova IG, Tautermann CS, Hunt P, Ceska T, Hodgson S, Bodkin MJ, Singh S, Law RJ, Biggin PC (2015) GPCR structure, function, drug discovery and crystallography: report from academia-industry international conference (UK Royal Society) Chicheley hall, 1-2 September 2014. Naunyn Schmiedeberg’s Arch Pharmacol 388:883–903.
2. Shonberg J, Kling RC, Gmeiner P, Lober S (2015) GPCR crystal structures: medicinal chemistry in the pocket. Bioorg Med Chem 23:3880–3906.
3. Wise A, Gearing K, Rees S (2002) Target validation of G-protein coupled receptors. Drug Discov Today 7:235–246.
4. trials suggests major shifts in molecular class and indication. Annu Rev Pharmacol Toxicol 54:9–26.
5. Dohlman HG (2015) Thematic minireview series: new directions in G protein-coupled receptor pharmacology. J Biol Chem 290:19469–19470.
6. Jazayeri A, Andrews SP, Marshall FH (2017) Structurally enabled discovery of adenosine A2A receptor antagonists. Chem Rev 117:21–37.
7. Jazayeri A, Dias JM, Marshall FH (2015) From G protein-coupled receptor structure resolution to rational drug design. J Biol Chem 290:19489–19495.
8. Cooke RM, Brown AJ, Marshall FH, Mason JS (2015) Structures of G protein-coupled receptors reveal new opportunities for drug discovery. Drug Discov Today 20:1355–1364.
9. Congreve M, Dias JM, Marshall FH (2014) Structure-based drug design for G protein-coupled receptors. Prog Med Chem 53:1–63.
10. Topiol S, Sabio M (2009) X-ray structure breakthroughs in the GPCR transmembrane region. Biochem Pharmacol 78:11–20.
11. Topiol S (2013) X-ray structural information of GPCRs in drug design: what are the limitations and where do we go? Expert Opin Drug Discov 8:607–620.
12. Topiol S, Sabio M (2015) The role of experimental and computational structural approaches in 7TM drug discovery. Expert Opin Drug Discov 10:1071–1084.
13. Tautermann CS, Gloriam DE (2016) Editorial overview: new technologies: GPCR drug design and function-exploiting the current (of) structures. Curr Opin Pharmacol 30:8–10.
14. Biggin PC, Aldeghi M, Bodkin MJ, Heifetz A (2016) Beyond membrane protein structure: drug discovery, dynamics and difficulties. Adv Exp Med Biol 922:161–181.
15. Tautermann CS, Seeliger D, Kriegl JM (2015) What can we learn from molecular dynamics simulations for GPCR drug design? Comput Struct Biotechnol J 13:111–121.
16. Latorraca NR, Venkatakrishnan AJ, Dror RO (2017) GPCR dynamics: structures in motion. Chem Rev 117:139–155.
17. Guo D, Pan AC, Dror RO, Mocking T, Liu R, Heitman LH, Shaw DE, IJ AP (2016) Molecular basis of ligand dissociation from the adenosine A2A receptor. Mol Pharmacol 89:485–491.
18. Pan AC, Borhani DW, Dror RO, Shaw DE (2013) Molecular determinants of drug-receptor binding kinetics. Drug Discov Today 18:667–673.
19. Dror RO, Arlow DH, Maragakis P, Mildorf TJ, Pan AC, Xu H, Borhani DW, Shaw DE (2011) Activation mechanism of the beta2-adrenergic receptor. Proc Natl Acad Sci U S A 108:18684–18689.
20. Mason JS, Bortolato A, Weiss DR, Deflorian F, Tehan B, Marshall FH (2013) High end GPCR design: crafted ligand design and druggability analysis using protein structure, lipophilic hotspots and explicit water networks. In Silico Pharmacol 1:23.
21. Heifetz A, James T, Morao I, Bodkin MJ, Biggin PC (2016) Guiding lead optimization with GPCR structure modeling and molecular dynamics. Curr Opin Pharmacol 30:14–21.
22. Deprez-Poulain R, Deprez B (2004) Facts, figures and trends in lead generation. Curr Top Med Chem 4:569–580.
23. Heifetz A, Aldeghi M, Chudyk E, Fedorov DG, Bodkin M, Biggin PC (2016) Using the fragment molecular orbital method to investigate agonist-orexin 2 receptor interactions. Biochem Soc Trans 44(2):574–581.
24. Heifetz A, Chudyk EI, Gleave L, Aldeghi M, Cherezov V, Fedorov DG, Biggin PC, Bodkin MJ (2016) The fragment molecular orbital method reveals new insight into the chemical nature of GPCR-ligand interactions. J Chem Inf Model 56:159–172.
25. Heifetz A, Storer RI, McMurray G, James T, Morao I, Aldeghi M, Bodkin MJ, Biggin PC (2016) Application of an integrated GPCR SAR-modeling platform to explain the activation selectivity of human 5-HT over 5-HT. ACS Chem Biol 11(5):1372–1382.
26. Storer RI, Brennan PE, Brown AD, Bungay PJ, Conlon KM, Corbett MS, DePianta RP, Fish PV, Heifetz A, Ho DK, Jessiman AS, McMurray G, de Oliveira CA, Roberts LR, Root JA, Shanmugasundaram V, Shapiro MJ, Skerten M, Westbrook D, Wheeler S, Whitlock GA, Wright J (2014) Multiparameter optimization in CNS drug discovery: design of pyrimido[4,5-d]azepines as potent 5-hydroxytryptamine 2C (5-HT(2)C) receptor agonists with exquisite functional selectivity over 5-HT(2)A and 5-HT(2)B receptors. J Med Chem 57:5258–5269.
27. Tautermann CS (2014) GPCR structures in drug design, emerging opportunities with new structures. Bioorg Med Chem Lett 24:4073–4079.
28. Bartuzi D, Kaczor AA, Targowska-Duda KM, Matosiuk D (2017) Recent advances and applications of molecular docking to G protein-coupled receptors. Molecules 22(2):E340.
29. Kitchen DB, Decornez H, Furr JR, Bajorath J (2004) Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov 3:935–949.
30. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662.
31. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461.
32. Rarey M, Kramer B, Lengauer T, Klebe G (1996) A fast flexible docking method using an incremental construction algorithm. J Mol Biol 261:470–489.
33. Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Improved protein-ligand docking using GOLD. Proteins 52:609–623.
34. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749.
35. Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case DA, Cheatham TE 3rd (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889–897.
36. Liu S, Wu Y, Lin T, Abel R, Redmann JP, Summa CM, Jaber VR, Lim NM, Mobley DL (2013) Lead optimization mapper: automating free energy calculations for lead optimization. J Comput Aided Mol Des 27(9). https://doi.org/10.1007/s10822-10013-19678-y.
37. Sotriffer CA, Flader W, Winger RH, Rode BM, Liedl KR, Varga JM (2000) Automated docking of ligands to antibodies: methods and applications. Methods 20:280–291.
38. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791.
39. Blundell CD, Packer MJ, Almond A (2013) Quantification of free ligand conformational preferences by NMR and their relationship to the bioactive conformation. Bioorg Med Chem 21:4976–4987.
40. Hawkins PC, Skillman AG, Nicholls A (2007) Comparison of shape-matching and docking as virtual screening tools. J Med Chem 50:74–82.
41. Marino KA, Shang Y, Filizola M (2017) Insights into the function of opioid receptors from molecular dynamics simulations of available crystal structures. Br J Pharmacol. https://doi.org/10.1111/bph.13774.
42. Schneider S, Provasi D, Filizola M (2015) The dynamic process of drug-GPCR binding at either orthosteric or allosteric sites evaluated by metadynamics. Methods Mol Biol 1335:277–294.
43. Kaczor AA, Rutkowska E, Bartuzi D, Targowska-Duda KM, Matosiuk D, Selent J (2016) Computational methods for studying G protein-coupled receptors (GPCRs). Methods Cell Biol 132:359–399.
44. Bartuzi D, Kaczor AA, Matosiuk D (2015) Activation and allosteric modulation of human mu opioid receptor in molecular dynamics. J Chem Inf Model 55:2421–2434.
45. Labute P (2010) LowModeMD--implicit low-mode velocity filtering applied to conformational search of macrocycles and protein loops. J Chem Inf Model 50:792–800.
46. De Vivo M, Masetti M, Bottegoni G, Cavalli A (2016) Role of molecular dynamics and related methods in drug discovery. J Med Chem 59:4035–4061.
47. Mollica L, Theret I, Antoine M, Perron-Sierra F, Charton Y, Fourquez J-M, Wierzbicki M, Boutin JA, Ferry G, Decherchi S, Bottegoni G, Ducrot P, Cavalli A (2016) Molecular dynamics simulations and kinetic measurements to estimate and predict protein–ligand residence times. J Med Chem 59:7167–7176.
48. Copeland RA (2016) The drug-target residence time model: a 10-year retrospective. Nat Rev Drug Discov 15:87–95.
49. Heifetz A, Trani G, Aldeghi M, MacKinnon CH, McEwan PA, Brookfield FA, Chudyk E, Bodkin M, Pei Z, Burch JD, Ortwine DF (2016) Fragment molecular orbital method applied to lead optimization of novel interleukin-2 inducible T-Cell Kinase (ITK) inhibitors. J Med Chem 59(9):4352–4363.
50. Morao I, Fedorov DG, Robinson R, Southey M, Townsend-Nicholson A, Bodkin MJ, Heifetz A (2017) Rapid and accurate assessment of GPCR-ligand interactions using the fragment molecular orbital-based density-functional tight-binding method. J Comput Chem 38(23):1987–1990.
51. Abel R, Young T, Farid R, Berne BJ, Friesner RA (2008) Role of the active-site solvent in the thermodynamics of factor Xa ligand binding. J Am Chem Soc 130:2817–2831.
52. Ross GA, Morris GM, Biggin PC (2012) Rapid and accurate prediction and scoring of water molecules in protein binding sites. PLoS One 7:e32036.
53. Truchon JF, Pettitt BM, Labute P (2014) A cavity corrected 3D-RISM functional for accurate solvation free energies. J Chem Theory Comput 10:934–941.
54. Gerogiokas G, Southey MW, Mazanetz MP, Heifetz A, Bodkin M, Law RJ, Henchman RH, Michel J (2016) Assessment of hydration thermodynamics at protein interfaces with grid cell theory. J Phys Chem B 120:10442–10452.
55. Gerogiokas G, Southey MW, Mazanetz MP, Heifetz A, Bodkin M, Law RJ, Michel J (2015) Evaluation of water displacement energetics in protein binding sites with grid cell theory. Phys Chem Chem Phys 17:8416–8426.
56. Vajda S, Guarnieri F (2006) Characterization of protein-ligand interaction sites using experimental and computational methods. Curr Opin Drug Discov Devel 9:354–362.
57. Goldmann D, Zdrazil B, Digles D, Ecker GF (2016) Empowering pharmacoinformatics by linked life science data. J Comput Aided Mol Des 31(3):319–328.
58. Mazanetz MP, Marmon RJ, Reisser CB, Morao I (2012) Drug discovery applications for KNIME: an open source data mining platform. Curr Top Med Chem 12:1965–1979.
59. Heifetz A, Barker O, Verquin G, Wimmer N, Meutermans W, Pal S, Law RJ, Whittaker M (2013) Fighting obesity with a sugar-based library: discovery of novel MCH-1R antagonists by a new computational-VAST approach for exploration of GPCR binding sites. J Chem Inf Model 53:1084–1099.
60. Tye H, Mueller SG, Prestle J, Scheuerer S, Schindler M, Nosse B, Prevost N, Brown CJ, Heifetz A, Moeller C, Pedret-Dunn A, Whittaker M (2011) Novel 6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene analogues as potent and selective 5-HT(2C) agonists for the treatment of metabolic disorders. Bioorg Med Chem Lett 21:34–37.
61. Davenport AJ, Moller C, Heifetz A, Mazanetz MP, Law RJ, Ebneth A, Gemkow MJ (2010) Using electrophysiology and in silico three-dimensional modeling to reduce human Ether-a-go-go related gene K(+) channel inhibition in a histamine H3 receptor antagonist program. Assay Drug Dev Technol 8:781–789.
62. Heifetz A, Morris GB, Biggin PC, Barker O, Fryatt T, Bentley J, Hallett D, Manikowski D, Pal S, Reifegerste R, Slack M, Law R (2012) Study of human Orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulations, and site-directed mutagenesis. Biochemistry 51:3178–3197.
63. Barnoud J, Monticelli L (2015) Coarse-grained force fields for molecular simulations. Methods Mol Biol 1215:125–149.
64. Gutierrez-de-Teran H, Keranen H, Azuaje J, Rodriguez D, Aqvist J, Sotelo E (2015) Computer-aided design of GPCR ligands. Methods Mol Biol 1272:271–291.
65. Tummino PJ, Copeland RA (2008) Residence time of receptor-ligand complexes and its effect on biological function. Biochemistry 47:5481–5492.
66. Guo D, Hillger JM, IJzerman AP, Heitman LH (2014) Drug-target residence time—a case for G protein-coupled receptors. Med Res Rev 34:856–892.