Computational Challenges of Structure-Based Approaches Applied to HIV

  • Stefano Forli
  • Arthur J. OlsonEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 389)


Three-dimensional model of mature HIV. A cutaway view of mature HIV includes the capsid (gray, with pentamers in yellow) and nucleocapsid (red), matrix protein (green), accessory proteins (magenta), membrane (white), and envelope protein (blue). The model was generated using CellPACK by Graham Johnson

Here, we review some of the opportunities and challenges that we face in computational modeling of HIV therapeutic targets and structural biology, both in terms of methodology development and structure-based drug design (SBDD). Computational methods have provided fundamental support to HIV research since the initial structural studies, helping to unravel details of HIV biology. Computational models have proved to be a powerful tool to analyze and understand the impact of mutations and to overcome their structural and functional influence in drug resistance. With the availability of structural data, in silico experiments have been instrumental in exploiting and improving interactions between drugs and viral targets, such as HIV protease, reverse transcriptase, and integrase. Issues such as viral target dynamics and mutational variability, as well as the role of water and estimates of binding free energy in characterizing ligand interactions, are areas of active computational research. Ever-increasing computational resources and theoretical and algorithmic advances have played a significant role in progress to date, and we envision a continually expanding role for computational methods in our understanding of HIV biology and SBDD in the future.


Virtual Screening Chemical Space Allosteric Site Catalytic Core Domain Focus Library 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Binding energy distribution analysis method


Catalytic core domain


Backscattering interferometry


Differential scanning fluorimetry


Developmental Therapeutics Program




Fragment-based drug design


Highly active antiretroviral therapy


Human immunodeficiency virus


High-throughput virtual screening




IN strand transfer inhibitor


Lens epithelium-derived growth factor


Molecular dynamics


Molecular weight


Normal mode analysis


Protein Data Bank


Protein–protein interaction




Relaxed complex


RNase H


Reverse transcriptase


Statistical Assessment of Modeling of Proteins and Ligands


Structure-based drug design


World Community Grid



We thank IBM World Community Grid for the computational resource support provided to the FightAIDS@Home project. This work was supported by NIH R01 GM073087 and P50 GM103368 to AJO.


  1. Adachi M, Ohhara T, Kurihara K, Tamada T, Honjo E, Okazaki N, Arai S, Shoyama Y, Kimura K, Matsumura H (2009) Structure of HIV-1 protease in complex with potent inhibitor KNI-272 determined by high-resolution X-ray and neutron crystallography. Proc Nat Acad Sci 106(12):4641–4646CrossRefPubMedCentralPubMedGoogle Scholar
  2. Ala PJ, DeLoskey RJ, Huston EE, Jadhav PK, Lam PY, Eyermann CJ, Hodge CN, Schadt MC, Lewandowski FA, Weber PC (1998) Molecular recognition of cyclic urea HIV-1 protease inhibitors. J Biol Chem 273(20):12325–12331CrossRefPubMedGoogle Scholar
  3. Alvizo O, Mittal S, Mayo SL, Schiffer CA (2012) Structural, kinetic, and thermodynamic studies of specificity designed HIV-1 protease. Protein Sci 21(7):1029–1041CrossRefPubMedCentralPubMedGoogle Scholar
  4. Amaro RE, Baron R, McCammon JA (2008) An improved relaxed complex scheme for receptor flexibility in computer-aided drug design. J comput Aided Mol Des 22(9):693–705CrossRefPubMedCentralPubMedGoogle Scholar
  5. Baksh MM, Kussrow AK, Mileni M, Finn M, Bornhop DJ (2011) Label-free quantification of membrane-ligand interactions using backscattering interferometry. Nat Biotechnol 29(4):357–360CrossRefPubMedCentralPubMedGoogle Scholar
  6. Baldwin ET, Bhat TN, Gulnik S, Liu B, Topol IA, Kiso Y, Mimoto T, Mitsuya H, Erickson JW (1995) Structure of HIV-1 protease with KNI-272, a tight-binding transition-state analog containing allophenylnorstatine. Structure 3(6):581–590CrossRefPubMedGoogle Scholar
  7. Belew RK, Chang MW (2006) Modeling recombination’s role in the evolution of HIV drug resistance. In: Rocha LM, Bedau M, Floreano D, Goldstone R, Vespignani A, Yaeger L (eds) Artificial life X: the tenth international conference on the synthesis and simulation of living systems. MIT Press, Citeseer, pp 98–104Google Scholar
  8. Binkowski TA, Naghibzadeh S, Liang J (2003) CASTp: computed atlas of surface topography of proteins. Nucleic Acids Res 31(13):3352–3355CrossRefPubMedCentralPubMedGoogle Scholar
  9. Capra JA, Laskowski RA, Thornton JM, Singh M, Funkhouser TA (2009) Predicting protein ligand binding sites by combining evolutionary sequence conservation and 3D structure. PLoS Comput Biol 5(12):e1000585CrossRefPubMedCentralPubMedGoogle Scholar
  10. Chang MW, Torbett BE (2011) Accessory mutations maintain stability in drug-resistant HIV-1 protease. J Mol Biol 410(4):756–760CrossRefPubMedCentralPubMedGoogle Scholar
  11. Chang MW, Lindstrom W, Olson AJ, Belew RK (2007) Analysis of HIV wild-type and mutant structures via in silico docking against diverse ligand libraries. J Chem Inf Model 47(3):1258–1262CrossRefPubMedGoogle Scholar
  12. Chen Y, Shoichet BK (2009) Molecular docking and ligand specificity in fragment-based inhibitor discovery. Nat Chem Biol 5(5):358–364CrossRefPubMedCentralPubMedGoogle Scholar
  13. Christ F, Voet A, Marchand A, Nicolet S, Desimmie BA, Marchand D, Bardiot D, Van der Veken NJ, Van Remoortel B, Strelkov SV (2010) Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat Chem Biol 6(6):442–448CrossRefPubMedGoogle Scholar
  14. Cosconati S, Forli S, Perryman AL, Harris R, Goodsell DS, Olson AJ (2010) Virtual screening with AutoDock: theory and practice. Expert Opin Drug Discov 5(6):597–607CrossRefPubMedCentralPubMedGoogle Scholar
  15. Cosconati S, Marinelli L, Di Leva FS, La Pietra V, De Simone A, Mancini F, Andrisano V, Novellino E, Goodsell DS, Olson AJ (2012) Protein flexibility in virtual screening: the BACE-1 case study. J Chem Inf Model 52(10):2697–2704CrossRefPubMedCentralPubMedGoogle Scholar
  16. Engelman A, Cherepanov P (2012) The structural biology of HIV-1: mechanistic and therapeutic insights. Nat Rev Microbiol 10(4):279–290CrossRefPubMedCentralPubMedGoogle Scholar
  17. FightAids@Home FA@H project page (2014) Accessed 21 July 2014
  18. Forli S, Olson AJ (2012) A force field with discrete displaceable waters and desolvation entropy for hydrated ligand docking. J Med Chem 55(2):623–638CrossRefPubMedCentralPubMedGoogle Scholar
  19. Forli S, Tiefenbrunn T, Stout CD, Olson AJ (2014) Allosteric inhibitors of HIV protease, unpublished results, TSRI Google Scholar
  20. Gallicchio E, Lapelosa M, Levy RM (2010) Binding energy distribution analysis method (BEDAM) for estimation of Protein-Ligand binding affinities. J Chem Theor Comput 6(9):2961–2977CrossRefGoogle Scholar
  21. Gallicchio E, Deng N, He P, Wickstrom L, Perryman AL, Santiago DN, Forli S, Olson AJ, Levy RM (2014) Virtual screening of integrase inhibitors by large scale binding free energy calculations: the SAMPL4 challenge. J Comput Aided Mol Des 28(4):475–490 Google Scholar
  22. Goodsell DS, Olson AJ (1990) Automated docking of substrates to proteins by simulated annealing. Proteins Struct Funct Bioinform 8(3):195–202CrossRefGoogle Scholar
  23. Grid IWC WCG (2014) Accessed 21 July 2014
  24. Grzesiek S, Bax A, Nicholson LK, Yamazaki T, Wingfield P, Stahl SJ, Eyermann CJ, Torchia DA, Hodge CN (1994) NMR evidence for the displacement of a conserved interior water molecule in HIV protease by a non-peptide cyclic urea-based inhibitor. J Am Chem Soc 116(4):1581–1582CrossRefGoogle Scholar
  25. Hajduk PJ, Greer J (2007) A decade of fragment-based drug design: strategic advances and lessons learned. Nat Rev Drug Discov 6(3):211–219CrossRefPubMedGoogle Scholar
  26. Hall HI, Song R, Rhodes P, Prejean J, An Q, Lee LM, Karon J, Brookmeyer R, Kaplan EH, McKenna MT (2008) Estimation of HIV incidence in the United States. JAMA 300(5):520–529CrossRefPubMedCentralPubMedGoogle Scholar
  27. Halperin I, Ma B, Wolfson H, Nussinov R (2002) Principles of docking: an overview of search algorithms and a guide to scoring functions. Proteins Struct Funct Bioinform 47(4):409–443CrossRefGoogle Scholar
  28. Hare S, Vos AM, Clayton RF, Thuring JW, Cummings MD, Cherepanov P (2010) Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Nat Acad Sci 107(46):20057–20062CrossRefPubMedCentralPubMedGoogle Scholar
  29. Harris R, Olson AJ, Goodsell DS (2008) Automated prediction of ligand-binding sites in proteins. Proteins Struct Funct Bioinform 70(4):1506–1517CrossRefGoogle Scholar
  30. Heal J, Jimenez-Roldan JE, Wells SA, Freedman R, Römer RA (2012) Inhibition of HIV-1 protease: the rigidity perspective. Bioinformatics 28(3):350–357CrossRefPubMedGoogle Scholar
  31. Heaslet H, Rosenfeld R, Giffin M, Lin Y-C, Tam K, Torbett BE, Elder JH, McRee DE, Stout CD (2007) Conformational flexibility in the flap domains of ligand-free HIV protease. Acta Crystallogr Sect. D: Biol Crystallogr 63(8):866–875CrossRefGoogle Scholar
  32. Hodge CN, Aldrich PE, Bacheler LT, Chang C-H, Eyermann CJ, Garber S, Grubb M, Jackson DA, Jadhav PK, Korant B (1996) Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450. Chem Biol 3(4):301–314CrossRefPubMedGoogle Scholar
  33. Holbeck S (2004) Update on NCI in vitro drug screen utilities. Eur J Cancer 40(6):785–793CrossRefPubMedGoogle Scholar
  34. Jadhav PK, Ala P, Woerner FJ, Chang C-H, Garber SS, Anton ED, Bacheler LT (1997) Cyclic urea amides: HIV-1 protease inhibitors with low nanomolar potency against both wild type and protease inhibitor resistant mutants of HIV. J Med Chem 40(2):181–191CrossRefPubMedGoogle Scholar
  35. Johnson G, Goodsell DS, Autin L, Forli S, Sanner M, Olson AJ (2014) FD 169: 3D molecular models of whole HIV-1 virions generated with cellPACK. Faraday Discuss 169:23–44 Google Scholar
  36. King NM, Prabu-Jeyabalan M, Bandaranayake RM, Nalam MN, Nalivaika EA, Ael Özen, Tr Haliloĝlu, NeK Yılmaz, Schiffer CA (2012) Extreme Entropy-Enthalpy Compensation in a Drug-Resistant Variant of HIV-1 Protease. ACS Chem Biol 7(9):1536–1546CrossRefPubMedCentralPubMedGoogle Scholar
  37. Kiso Y, Matsumoto H, Mizumoto S, Kimura T, Fujiwara Y, Akaji K (1999) Small dipeptide-based HIV protease inhibitors containing the hydroxymethylcarbonyl isostere as an ideal transition-state mimic. Pept Sci 51(1):59–68CrossRefGoogle Scholar
  38. Kuntz ID, Blaney JM, Oatley SJ, Langridge R, Ferrin TE (1982) A geometric approach to macromolecule-ligand interactions. J Mol Biol 161(2):269–288CrossRefPubMedGoogle Scholar
  39. Lange-Savage G, Berchtold H, Liesum A, Budt KH, Peyman A, Knolle J, Sedlacek J, Fabry M, Hilgenfeld R (1997) Structure of HOE/BAY 793 complexed to Human Immunodeficiency Virus (HIV-1) protease in two different crystal forms structure/function relationship and influence of crystal packing. Eur J Biochem 248(2):313–322CrossRefPubMedGoogle Scholar
  40. Laurie AT, Jackson RM (2005) Q-SiteFinder: an energy-based method for the prediction of protein–ligand binding sites. Bioinformatics 21(9):1908–1916CrossRefPubMedGoogle Scholar
  41. Leslie A, Pfafferott K, Chetty P, Draenert R, Addo M, Feeney M, Tang Y, Holmes E, Allen T, Prado J (2004) HIV evolution: CTL escape mutation and reversion after transmission. Nat Med 10(3):282–289CrossRefPubMedGoogle Scholar
  42. Liang S, Zhang C, Liu S, Zhou Y (2006) Protein binding site prediction using an empirical scoring function. Nucleic Acids Res 34(13):3698–3707CrossRefPubMedCentralPubMedGoogle Scholar
  43. Lin J-H, Perryman AL, Schames JR, McCammon JA (2002) Computational drug design accommodating receptor flexibility: the relaxed complex scheme. J Am Chem Soc 124(20):5632–5633CrossRefPubMedGoogle Scholar
  44. Lu C, Li AP (2010) Enzyme inhibition in drug discovery and development: the good and the bad. Wiley, New YorkGoogle Scholar
  45. Marshall GR (1987) Computer-aided drug design. Ann Rev Pharmacol Toxicol 27(1):193–213CrossRefGoogle Scholar
  46. Mittal S, Cai Y, Nalam MN, Bolon DN, Schiffer CA (2012) Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease. J Am Chem Soc 134(9):4163–4168CrossRefPubMedCentralPubMedGoogle Scholar
  47. Mobley DL, Liu S, Lim NM, Wymer KL, Perryman AL, Forli S, Deng N, Su J, Branson K, Olson AJ (2014) Blind prediction of HIV integrase binding from the SAMPL4 challenge. J Comput Aided Mol Des 28(4):327–345Google Scholar
  48. Moon JB, Howe WJ (1991) Computer design of bioactive molecules: a method for receptor-based de novo ligand design. Proteins Struct Funct Bioinform 11(4):314–328CrossRefGoogle Scholar
  49. 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(14):1639–1662CrossRefGoogle Scholar
  50. 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(16):2785–2791CrossRefPubMedCentralPubMedGoogle Scholar
  51. Navia MA, Fitzgerald PM, McKeever BM, Leu CT, Heimbach JC, Herber WK, Sigal IS, Darke PL, Springer JP (1989) Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 337(6208):615–620. doi: 10.1038/337615a0 CrossRefPubMedGoogle Scholar
  52. Nicholson LK, Yamazaki T, Torchia DA, Grzesiek S, Bax A, Stahl SJ, Kaufman JD, Wingfield PT, Lam PY, Jadhav PK (1995) Flexibility and function in HIV-1 protease. Nat Struct Biol 2(4):274–280CrossRefPubMedGoogle Scholar
  53. NIH Developmental Therapeutics Program (2014) Accessed 11 June 2014
  54. NIH2 DTP NCI Diversity set IV (2014) Accessed 10 June 2014
  55. Österberg F, Morris GM, Sanner MF, Olson AJ, Goodsell DS (2002) Automated docking to multiple target structures: incorporation of protein mobility and structural water heterogeneity in AutoDock. Proteins Struct Funct Bioinform 46 (1):34–40Google Scholar
  56. Perryman AL, Lin JH, McCammon JA (2004) HIV-1 protease molecular dynamics of a wild-type and of the V82F/I84V mutant: possible contributions to drug resistance and a potential new target site for drugs. Protein Sci 13(4):1108–1123CrossRefPubMedCentralPubMedGoogle Scholar
  57. Perryman AL, Lin JH, McCammon JA (2006) Restrained molecular dynamics simulations of HIV-1 protease: the first step in validating a new target for drug design. Biopolymers 82(3):272–284CrossRefPubMedGoogle Scholar
  58. Perryman AL, Forli S, Morris GM, Burt C, Cheng Y, Palmer MJ, Whitby K, McCammon JA, Phillips C, Olson AJ (2010a) A dynamic model of HIV integrase inhibition and drug resistance. J Mol Biol 397(2):600–615CrossRefPubMedCentralPubMedGoogle Scholar
  59. Perryman AL, Zhang Q, Soutter HH, Rosenfeld R, McRee DE, Olson AJ, Elder JE, David Stout C (2010b) Fragment-Based Screen against HIV Protease. Chem Biol Drug Des 75(3):257–268CrossRefPubMedCentralPubMedGoogle Scholar
  60. Perryman AL, Santiago DN, Forli S, Santos-Martins D, Olson AJ (2014) Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein–ligand binding challenge. J Comput Aided Mol Des 28(4):429–441Google Scholar
  61. Sanner MF, Olson AJ, Spehner JC (1996) Reduced surface: an efficient way to compute molecular surfaces. Biopolymers 38(3):305–320CrossRefPubMedGoogle Scholar
  62. Suresh CH, Vargheese AM, Vijayalakshmi KP, Mohan N, Koga N (2008) Role of structural water molecule in HIV protease-inhibitor complexes: a QM/MM study. J Comput Chem 29(11):1840–1849CrossRefPubMedGoogle Scholar
  63. Tiefenbrunn T, Forli S, Baksh MM, Chang MW, Happer M, Lin Y-C, Perryman AL, Rhee J-K, Torbett BE, Olson AJ (2013) Small molecule regulation of protein conformation by binding in the flap of HIV protease. ACS Chem Biol 8(6):1223–1231CrossRefPubMedCentralPubMedGoogle Scholar
  64. Tiefenbrunn T, Forli S, Happer M, Gonzalez A, Tsai Y, Soltis M, Elder JH, Olson AJ, Stout CD (2014) Crystallographic fragment-based drug discovery: use of a brominated fragment library targeting HIV protease. Chem Biol Drug Des 83(2):141–148CrossRefPubMedCentralPubMedGoogle Scholar
  65. 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(2):455–461PubMedCentralPubMedGoogle Scholar
  66. Volkamer A, Kuhn D, Rippmann F, Rarey M (2012) DoGSiteScorer: a web server for automatic binding site prediction, analysis and druggability assessment. Bioinformatics 28(15):2074–2075CrossRefPubMedGoogle Scholar
  67. Wang Y-X, Freedberg DI, Wingfield PT, Stahl SJ, Kaufman JD, Kiso Y, Bhat TN, Erickson JW, Torchia DA (1996) Bound water molecules at the interface between the HIV-1 protease and a potent inhibitor, KNI-272, determined by NMR. J Am Chem Soc 118(49):12287–12290CrossRefGoogle Scholar
  68. Wang R, Lu Y, Wang S (2003) Comparative evaluation of 11 scoring functions for molecular docking. J Med Chem 46(12):2287–2303CrossRefPubMedGoogle Scholar
  69. Warren GL, Andrews CW, Capelli A-M, Clarke B, LaLonde J, Lambert MH, Lindvall M, Nevins N, Semus SF, Senger S (2006) A critical assessment of docking programs and scoring functions. J Med Chem 49(20):5912–5931CrossRefPubMedGoogle Scholar
  70. Weber IT (1990) Evaluation of homology modeling of HIV protease. Proteins Struct Funct Bioinform 7(2):172–184CrossRefGoogle Scholar
  71. Whiting M, Muldoon J, Lin Y-C, Silverman SM, Lindstrom W, Olson AJ, Kolb HC, Finn M, Sharpless KB, Elder JH (2006) Inhibitors of HIV-1 protease by using in situ click chemistry. Angew Chem Int Ed 45(9):1435–1439CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.MGL, Department of Integrative Structural and Computational Biology and HIV Interaction and Viral Evolution CenterThe Scripps Research InstituteLa JollaUSA

Personalised recommendations