Skip to main content

Drug Design

  • 639 Accesses

Part of the SpringerBriefs in Space Life Sciences book series (BRIEFSSLS)

Abstract

X-ray crystallographic data are today mandatory for drug discovery and are essential within the iterative process of drug design. Microgravity grown crystals of potential drug target proteins or complexes of drug target proteins with selected compounds supported the design and development of new generations of pharmaceuticals, which were forwarded to clinical trials to treat chronic and infectious diseases such as T-cell lymphoma, HIV, psoriasis, stroke and other cardiovascular complications, influenza and rheumatic arthritis. Results derived from crystals grown under microgravity conditions also contributed, for example, to the understanding of drug cancer- cell interactions.

Keywords

  • Three-dimensional Structures
  • X-ray Analysis
  • Drug Design Investigations

This is a preview of subscription content, access via your institution.

Fig. 4.1
Fig.4.2
Fig. 4.3
Fig. 4.4
Fig. 4.5
Fig. 4.6

References

  • Akparov VK, Timofeev VI, Kuranova IP (2015) Crystallization and preliminary X-ray diffraction study of porcine carboxypeptidase B. Crystallogr Rep 60(3):367–369. doi:10.1134/s1063774515030025

    CrossRef  Google Scholar 

  • Alvarado UR, DeWitt CR, Shultz BB, Ramsland PA, Edmundson AB (2001) Crystallization of a human Bence–Jones protein in microgravity using vapor diffusion in capillaries. J Cryst Growth 223(3):407–414. doi:10.1016/S0022-0248(00)01011-3

    CrossRef  Google Scholar 

  • Bedell CR (1992) The design of drugs to macromolecular targets. Wiley, Chichester

    Google Scholar 

  • Bence-Jones H (1848) On a new substance occurring in the urine of a patient with Mollities Ossium. Phil Trans R Soc Lond 138:55–62. doi:10.1098/rstl.1848.0003

    CrossRef  Google Scholar 

  • Berisio R, Vitagliano L, Sorrentino G, Carotenuto L, Piccolo C, Mazza-Rella L, Zagari A (2000) Effects of microgravity on the crystal quality of a collagen-like polypeptide. Acta Crystallogr D Biol Crystallogr 56:55–61

    CrossRef  Google Scholar 

  • Berisio R, Vitagliano L, Mazzarella L, Zagari A (2002) Crystal structure of the collagen triple helix model [(Pro-Pro-Gly)(10)](3). Protein Sci 11(2):262–270. doi:10.1110/ps.32602

    CrossRef  Google Scholar 

  • Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucl Acid Res 28:235–242

    CrossRef  Google Scholar 

  • Blundell TL, Johnson LN (1976) Protein crystallography. Academic, London

    Google Scholar 

  • Blundell TL, Jhoti H, Abell C (2002) High throughput crystallography for lead discovery in drug design. Nat Rev Drug Discov 1:45–54

    CrossRef  Google Scholar 

  • Borgstahl GEO, Vahedi-Faridi A, Lovelace J, Bellamy HD, Snell EH (2001) A test of macromolecular crystallization in microgravity: large well ordered insulin crystals. Acta Crystallogr Sect D 57(8):1204–1207. doi:10.1107/S0907444901007892

    CrossRef  Google Scholar 

  • Broutin I, Riès-Kautt M, Ducruix A (1997) Crystallographic analyses of lysozyme and collagenase microgravity grown crystals versus ground controls. J Cryst Growth 181(1):97–108. doi:10.1016/S0022-0248(97)00281-9

    CrossRef  Google Scholar 

  • Broutin-L’Hermite I, Ries-Kautt M, Ducruix A (2000) 1.7 A X-ray structure of space-grown collagenase crystals. Acta Crystallogr Sect D56(3):376–378. doi:10.1107/S0907444999016789

    Google Scholar 

  • Büttner H, Mack D, Rohde H (2015) Structural basis of Staphylococcus epidermis biofilm formation: mechanisms and molecular interactions. Front Cell Infect Microbiol 5:14. doi:10.3389/fcimb.2015.00014

  • Carter DC, Wright B, Miller T, Chapman J, Twigg P, Keeling K, Moody K, White M, Click J, Ruble JR (1999a) Diffusion-controlled crystallization apparatus for microgravity (DCAM): flight and ground-based applications. J Cryst Growth 196(2):602–609

    CrossRef  Google Scholar 

  • Carter DC, Wright B, Miller T, Chapman J, Twigg P, Keeling K, Moody K, White M, Click J, Ruble JR, Ho JX, Adcock-Downey L, Dowling T, Chang C-H, Ala P, Rose J, Wang BC, Declercq J-P, Evrard C, Rosenberg J, Wery J-P, Clawson D, Wardell M, Stallings W, Stevens A (1999b) PCAM: a multi-user facility-based protein crystallization apparatus for microgravity. J Cryst Growth 196(2–4):610–622. doi:10.1016/S0022-0248(98)00858-6

    CrossRef  Google Scholar 

  • Chayen N, Helliwell JR (2002) Microgravity protein crystallization are we reaping the full benefit of outer space? Ann N Y Acad Sci 975:591–597

    CrossRef  Google Scholar 

  • Ciociola AA, Cohen LB, Kulkarni P (2014) How drugs are developed and approved by the FDA: current process and future directions. Am J Gastroenterol 4:620–623. doi:10.1038/ajg.2013.407

    CrossRef  Google Scholar 

  • Claus H, Akca E, Karbach G, Schlott B, Debaerdemaeker T, Declerq JP, König H (2001) Surface (glyco-)proteins: primary structure and crystallization under microgravity conditions. In: Proceedings of First European Workshop on Exo-/Astro-Biology Frascati, ESA SP-496

    Google Scholar 

  • Creighton TE (1992) Proteins: structures and molecular properties, 2nd edn. WH Freemann, New York

    Google Scholar 

  • Declercq J-P, Evrard C, Carter DC, Wright BS, Etienne G, Parello J (1999) A crystal of a typical EF-hand protein grown under microgravity diffracts X-rays beyond 0.9 Å resolution. J Cryst Growth 196(2–4):595–601. doi:10.1016/S0022-0248(98)00829-X

    CrossRef  Google Scholar 

  • DeLucas LJ (2001) Protein crystallization – is it rocket science? Drug Discov Today 6(14):734–744. doi:10.1016/S1359-6446(01)01838-4

    CrossRef  Google Scholar 

  • DeLucas LJ, Suddath FL, Snyder R, Naumann R, Broom MB, Pusey M, Yost V, Herren B, Carter D, Nelson B, Meehan EJ, McPherson A, Bugg CE (1986) Preliminary investigations of protein crystal growth using the space shuttle. J Cryst Growth 76(3):681–693. doi:10.1016/0022-0248(86)90185-5

    CrossRef  Google Scholar 

  • DeLucas L, Smith C, Smith H, Vijay-Kumar S, Senadhi S, Ealick S, Carter D, Snyder R, Weber P, Salemme F et al (1989) Protein crystal growth in microgravity. Science 246(4930):651–654. doi:10.1126/science.2510297

    CrossRef  Google Scholar 

  • DeLucas LJ, Long MM, Moore KM, Rosenblum WM, Bray TL, Smith C, Carson M, Narayana SVL, Harrington MD, Carter D, Clark AD, Nanni RG, Ding J, Jacobo-Molina A, Kamer G, Hughes SH, Arnold E, Einspahr HM, Clancy LL, Rao GSJ, Cook PF, Harris BG, Munson SH, Finzel BC, McPherson A, Weber PC, Lewandowski FA, Nagabhushan TL, Trotta PP, Reichert P, Navia MA, Wilson KP, Thomson JA, Richards RN, Bowersox KD, Meade CJ, Baker ES, Bishop SP, Dunbar BJ, Trinh E, Prahl J, Sacco A, Bugg CE (1994) Recent results and new hardware developments for protein crystal growth in microgravity. J Cryst Growth 135(1):183–195. doi:10.1016/0022-0248(94)90740-4

    CrossRef  Google Scholar 

  • DeLucas LJ, Moore KM, Long MM (1999) Protein crystal growth and the international space station. Gravit Space Biol Bull 12:39–45

    Google Scholar 

  • DeLucas LJ, Moore KM, Long MM, Rouleau R, Bray T, Crysel W, Weise L (2002) Protein crystal growth in space past and future. J Cryst Growth 239:1646–1650

    CrossRef  Google Scholar 

  • Drebes J, Künz M, Windshügel B, Kikhney AG, Müller IB, Eberle RJ, Oberthür D, Cang H, Svergun DI, Perbandt M, Betzel C, Wrenger C (2016) Structure of ThiM from Vitamin B1 biosynthetic pathway of Staphylococcus aureus – insights into a novel pro-drug approach addressing MRSA infections. Sci Rep 6:22871. doi:10.1038/srep22871

  • Drenth J (1994) Principles of protein X-ray crystallography. Springer, Berlin

    CrossRef  Google Scholar 

  • Ducruix A, Giege R (1999) Crystallization of nucleic acids and proteins. Oxford Academic Press, Oxford

    Google Scholar 

  • Ealick S, Cook W, Vijay-Kumar S, Carson M, Nagabhushan T, Trotta P, Bugg C (1991) Three-dimensional structure of recombinant human interferon-gamma. Science 252(5006):698–702. doi:10.1126/science.1902591

    CrossRef  Google Scholar 

  • Erdmann VA, Lippmann C, Betzel C, Dauter Z, Wilson K, Hilgenfeld R, Hoven J, Liesum A, Saenger W, Müller-Fahrnow A, Hinrichs W, Düvel M, Schulz GE, Müller CW, Wittmann HG, Yonath A, Weber G, Stegen K, Plaas-Link A (1989) Crystallization of proteins under microgravity. FEBS Lett 259(1):194–198. doi:10.1016/0014-5793(89)81526-1

    CrossRef  Google Scholar 

  • Erlanson DA, Braisted AC, Raphael DR, Randal M, Stroud RM, Gordon EM, Wells JA (2000) Site-directed ligand discovery. PNAS 97:9367–9372

    CrossRef  Google Scholar 

  • Esposito L, Sica F, Raia CA, Giordano A, Rossi M, Mazzarella L, Zagari A (2002) Crystal structure of the alcohol dehydrogenase from the hyperthermophilic archaeon Sulfolobus solfataricus at 1.85 A resolution. J Mol Biol 318(2):463–477. doi:10.1016/s0022-2836(02)00088-8

    CrossRef  Google Scholar 

  • Evrard C, Declercq JP, Debaerdemaeker T, König H (1999) The first successful crystallization of a prokaryotic extremely thermophilic outer surface layer glycoprotein. Z Kristaogr 214:427–429

    Google Scholar 

  • Funari S, Rapp G, Perbandt M, Dierks K, Vallazza M, Betzel C, Erdmann VA, Svergun DI (2000) Structure of free Thermus flavus 5S rRNA at 1.3 nm resolution from synchrotron X-ray solution scattering. J Biol Chem 275:31283–31288

    CrossRef  Google Scholar 

  • Hajto T, Hostanska K, Gabius HJ (1989) Modulatory potency of the b-galactoside-specific lectin from mistletoe extract (iscador) on the host defense system in vivo in rabbits and patients. Cancer Res 49:4803–4808

    Google Scholar 

  • Hajto T, Hostanka K, Frei K, Gabius HJ (1990) Increased secretion of tumor necrosis factor a, interleukin 1, and interleukin 6 by human mononuclear cells exposed to b-galactoside-specific lectin from clinically applied mistletoe extract. Cancer Res 50:3322–3326

    Google Scholar 

  • Han Y, Cang HX, Zhou JX, Wang YP, Bi RC, Colelesage J, Delbaere LTJ, Nahoum V, Shi R, Zhou M, Zhu DW, Lin SX (2004) Protein crystal growth on board Shenzhou 3: a concerted effort improves crystal diffraction quality and facilitates structure determination. Biochem Biophys Res Commun 324(3):1081–1086. doi:10.1016/j.bbrc.2004.09.166

    CrossRef  Google Scholar 

  • Harp JM, Hanson BL, Timm DE, Bunick GJ (2000) Asymmetries in the nucleosome core particle at 2.5 A resolution. Acta Crystallogr Sect D 56(12):1513–1534. doi:10.1107/S0907444900011847

    CrossRef  Google Scholar 

  • Henning M, Visanji M, Weber W, Janczikowski H, Plaas-Link A, Betzel C (1994) COSIMA—protein crystal growth facility for automatic processing on unmanned satellites. J Cryst Growth 135(3):513–522. doi:10.1016/0022-0248(94)90142-2

    CrossRef  Google Scholar 

  • Hilgenfeld R, Liesum A, Storm R, Plaas-Link A (1992) Crystallization of two bacterial enzymes on an unmanned space mission. J Cryst Growth 122(1):330–336. doi:10.1016/0022-0248(92)90265-K

    CrossRef  Google Scholar 

  • Inaka K, Takahashi S, Aritake K, Tsurumura T, Furubayashi N, Yan B, Hirota E, Sano S, Sato M, Kobayashi T, Yoshimura Y, Tanaka H, Urade Y (2011) High-quality protein crystal growth of mouse lipocalin-type prostaglandin D synthase in microgravity. Cryst Growth Des 11(6):2107–2111. doi:10.1021/cg101370v

    CrossRef  Google Scholar 

  • Kinoshita T, Maruki R, Warizaya M, Nakajima H, Nishimura S (2005) Structure of a high-resolution crystal form of human triosephosphate isomerase: improvement of crystals using the gel-tube method. Acta Crystallogr Sect F: Struct Biol Cryst Commun 61(4):346–349

    CrossRef  Google Scholar 

  • Kitano K, Sasaki R, Nogi T, Fukami TA, Nakagawa A, Miki K, Tanaka I (2000) Utilization of microgravity to improve the crystal quality of biologically important proteins: chaperonin-60, GrpE, B-subunit of V-type ATPase, and MIF. J Cryst Growth 210(4):819–823. doi:10.1016/S0022-0248(99)00902-1

    CrossRef  Google Scholar 

  • Klebe G (2006) Virtual ligand screening, strategies, perspectives and limitations. Drug Discov Today 11:580–592

    CrossRef  Google Scholar 

  • Krauspenhaar R, Rypniewski W, Kalkura N, Moore K, DeLucas L, Stoeva S, Mikhailov A, Voelter W, Betzel C (2002) Crystallisation under microgravity of mistletoe lectin I from Viscum album with adenine monophosphate and the crystal structure at 1.9 Å resolution. Acta Crystallogr D Biol Crystallogr 58(10):1704–1707

    CrossRef  Google Scholar 

  • Kuntz ID, Chen K, Sharp KA, Kollmann PA (1999) The maximal affinity of ligands. Proc Natl Acad Sci U S A 96:9997–10002

    CrossRef  Google Scholar 

  • Larson SB, Day J, Greenwood A, McPherson A (1998) Refined structure of satellite tobacco mosaic virus at 1.8 Å resolution1. J Mol Biol 277(1):37–59. doi:10.1006/jmbi.1997.1570

    CrossRef  Google Scholar 

  • Littke EW, John C (1984) Materials. Protein single crystal growth under microgravity. Science 225(4658):203–204. doi:10.1126/science.225.4658.203

    CrossRef  Google Scholar 

  • Littke W, John C (1986) Protein single crystal growth under microgravity. J Cryst Growth 76(3):663–672. doi:10.1016/0022-0248(86)90183-1

    CrossRef  Google Scholar 

  • Long MM, Bishop JB, DeLucas LJ, Nagabhushan TL, Reichert P, Smith GD (1997) Protein crystal growth in microgravity review of large scale temperature induction method: bovine insulin, human insulin and human α-interferon. AIP Conf Proc 387(1):671–678. doi:10.1063/1.52064

    Google Scholar 

  • Lorenz S, Perbandt M, Lippmann C, Moore K, DeLucas LJ, Betzel C, Erdmann VA (2000) Crystallization of engineered Thermus flavus 5S rRNA under Earth and microgravity conditions. Acta Crystallogr Sect D 56(4):498–500. doi:10.1107/S0907444900001736

    CrossRef  Google Scholar 

  • Mapelli M, Tucker PA (1999) Crystallization and preliminary X-ray crystallographic studies on the herpes simplex virus 1 single-stranded DNA binding protein. J Struct Biol 128(2):219–222. doi:10.1006/jsbi.1999.4192

    CrossRef  Google Scholar 

  • Mohamad Aris SNA, Thean Chor AL, Mohamad Ali MS, Basri M, Salleh AB, Raja Abd Rahman RNZ (2014) Crystallographic analysis of ground and space thermostable T1 lipase crystal obtained via counter diffusion method approach. Biomed Res Int 2014:8. doi:10.1155/2014/904381

    CrossRef  Google Scholar 

  • Ng JD (2002) Space-grown protein crystals are more useful for structure determination. Ann N Y Acad Sci 974:958–609

    CrossRef  Google Scholar 

  • Ng JD, Lorber B, Giege R, Koszelak S, Day J, Greenwood A, McPherson A (1997) Comparative analysis of thaumatin crystals grown on Earth and in microgravity. Acta Crystallogr Sect D 53(6):724–733. doi:10.1107/S090744499700694X

    CrossRef  Google Scholar 

  • Pan J-S, Niu X-T, Gui L-L, Zhou Y-C, Bi R-C (1996) Crystallization of biological macromolecules crystallization under microgravity of acidic phospholipase A2 from venom of Agkistrodon halys Pallas. J Cryst Growth 168(1):227–232. doi:10.1016/0022-0248(96)00374-0

    CrossRef  Google Scholar 

  • Ponassi M, Felli L, Parodi S, Valbusa U, Rosano C (2011) Crystals of the hydrogenase maturation factor HypF N-terminal domain grown in microgravity, display improved internal order. J Cryst Growth 314(1):246–251. doi:10.1016/j.jcrysgro.2010.12.011

    CrossRef  Google Scholar 

  • Pool R (1989) Zero gravity produces weighty improvements. Science 246:4930. doi:10.1126/science.2814485

    Google Scholar 

  • Rostock M, Huber R (2004) Randomized and double-blind studies – demands and reality as demonstrated by two examples of mistletoe research. Forsch Komplementärmed 11:18–22

    Google Scholar 

  • Rypniewski W, Vallazza M, Perbandt M, Klussmann S, DeLucas L, Betzel C, Erdmann VA (2006) The first crystal structure of an RNA racemate. Acta Cryst D62:659–664

    Google Scholar 

  • Skinner R, Abrahams J-P, Whisstock JC, Lesk AM, Carrell RW, Wardell MR (1997) The 2.6 Å structure of antithrombin indicates a conformational change at the heparin binding site 1. J Mol Biol 266(3):601–609. doi:10.1006/jmbi.1996.0798

    CrossRef  Google Scholar 

  • Smith GD, Ciszak E, Pangborn W (1996) A novel complex of a phenolic derivative with insulin: structural features related to the T-->R transition. Protein Sci 5(8):1502–1511

    CrossRef  Google Scholar 

  • Smith GD, Pangborn WA, Blessing RH (2003) The structure of T6 human insulin at 1.0 A resolution. Acta Crystallogr D Biol Crystallogr 59(Pt 3):474–482

    CrossRef  Google Scholar 

  • Stoddard BL, Strong RK, Arrott A, Farber GK (1992) Mir for the crystallographers’ money. Nature 360(6402):293–294

    CrossRef  Google Scholar 

  • Symersky J, Devedjiev Y, Moore K, Brouillette C, DeLucas L (2002) NH3-dependent NAD+ synthetase from Bacillus subtilis at 1 A resolution. Acta Crystallogr D Biol Crystallogr 58(Pt 7):1138–1146

    CrossRef  Google Scholar 

  • Tanaka H, Tsurumura T, Aritake K, Furubayashi N, Takahashi S, Yamanaka M, Hirota E, Sano S, Sato M, Kobayashi T, Tanaka T, Inaka K, Urade Y (2011) Improvement in the quality of hematopoietic prostaglandin D synthase crystals in a microgravity environment. J Synchrotron Radiat 18(1):88–91. doi:10.1107/s0909049510037076

    CrossRef  Google Scholar 

  • Terzyan SS, Bourne CR, Ramsland PA, Bourne PC, Edmundson AB (2003) Comparison of the three-dimensional structures of a human Bence-Jones dimer crystallized on Earth and aboard US Space Shuttle Mission STS-95. J Mol Recogn 16(2):83–90. doi:10.1002/jmr.610

    CrossRef  Google Scholar 

  • Timofeev V, Chuprov-Netochin R, Samigina V, Bezuglov V, Miroshnikov K, Kuranova I (2010a) X-ray investigation of gene-engineered human insulin crystallized from a solution containing polysialic acid. Acta Crystallogr Sect F: Struct Biol Cryst Commun 66(3):259–263

    CrossRef  Google Scholar 

  • Timofeev VI, Smirnova EA, Chupova LA, Esipov RS, Kuranova IP (2010b) Preparation of the crystal complex of phosphopantetheine adenylyltransferase from Mycobacterium tuberculosis with coenzyme A and investigation of its three-dimensional structure at 2.1-Å resolution. Crystallogr Rep 55(6):1050–1059. doi:10.1134/s1063774510060234

  • Timofeev V, Smirnova E, Chupova L, Esipov R, Kuranova I (2012a) X-ray study of the conformational changes in the molecule of phosphopantetheine adenylyltransferase from Mycobacterium tuberculosis during the catalyzed reaction. Acta Crystallogr D Biol Crystallogr 68(Pt 12):1660–1670. doi:10.1107/s0907444912040206

  • Timofeev VI, Smirnova EA, Chupova LA, Esipov RS, Kuranova IP (2012b) Three-dimensional structure of phosphopantetheine adenylyltransferase from Mycobacterium tuberculosis in the apo form and in complexes with coenzyme A and dephosphocoenzyme A. Crystallogr Rep 57(1):96–104. doi:10.1134/s1063774512010142

    CrossRef  Google Scholar 

  • Timofeev VI, Abramchik YA, Fateev IV, Zhukhlistova NE, Murav’eva TI, Kuranova IP, Esipov RS (2013a) Three-dimensional structure of thymidine phosphorylase from E. coli in complex with 3′-azido-2′-fluoro-2′,3′-dideoxyuridine. Crystallogr Rep 58(6):842–853. doi:10.1134/s1063774513060230

  • Timofeev VI, Kuznetsov SA, Akparov VK, Chestukhina GG, Kuranova IP (2013b) Three-dimensional structure of carboxypeptidase T from Thermoactinomyces vulgaris in complex with N-BOC-L-leucine. Biochem Mosc 78(3):252–259. doi:10.1134/s0006297913030061

  • Timofeev VI, Abramchik YA, Zhukhlistova NE, Muravieva TI, Esipov RS, Kuranova IP (2016) Three-dimensional structure of phosphoribosyl pyrophosphate synthetase from E. coli at 2.71 Å resolution. Crystallogr Rep 61(1):44–54. doi:10.1134/s1063774516010247

  • Vallazza M, Banumathi S, Perbandt M, Moore K, DeLucas L, Betzel C, Erdmann VA (2002) Crystallization and structure analysis of Thermus flavus 5S rRNA helix B. Acta Crystallogr D Biol Crystallogr 58(Pt 10 Pt 1):1700–1703

    Google Scholar 

  • Vallazza M, Perbandt M, Klussmann S, Rypniewski W, Einspahr HM, Erdmann VA, Betzel C (2004) First look at RNA in L-configuration. Acta Cryst D60:1–7

    Google Scholar 

  • Wardell MR, Skinner R, Carter DC, Twigg PD, Abrahams JP (1997) Improved diffraction of antithrombin crystals grown in microgravity. Acta Crystallogr D Biol Crystallogr 53(Pt 5):622–625. doi:10.1107/s0907444997003302

    CrossRef  Google Scholar 

  • Yoshikawa S, Kukimoto-Niino M, Parker L, Handa N, Terada T, Fujimoto T, Terazawa Y, Wakiyama M, Sato M, Sano S (2013) Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor. Oncogene 32(1):27–38

    CrossRef  Google Scholar 

  • Zhu D-W, Zhou M, Mao Y, Labrie F, Lin S-X (1995) Crystallization of human estrogenic 17β-hydroxysteroid dehydrogenase under microgravity. J Cryst Growth 156(1):108–111. doi:10.1016/0022-0248(95)00252-9

    CrossRef  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christian Betzel B.D.S., F.R.A.C.D.S., M.S. .

Rights and permissions

Reprints and Permissions

Copyright information

© 2017 The Author(s)

About this chapter

Cite this chapter

Betzel, C., Martirosyan, A. (2017). Drug Design. In: Biotechnology in Space. SpringerBriefs in Space Life Sciences. Springer, Cham. https://doi.org/10.1007/978-3-319-64054-9_4

Download citation