Abstract
Computer-aided techniques of rational design of enzyme inhibitors were reviewed. In silico lead generation and optimization protocols were outlined and several methods of inhibitor potency estimation by both empirical scoring functions as well as ab initio based calculations were described. Two representative examples of successful computer-aided analysis and design of novel, highly potent inhibitors of leucine aminopeptidase and glutamine synthetase were demonstrated. In addition fully nonempirical and systematic analysis of the physical nature of enzyme active site interactions has been performed for series of leucine aminopeptidase (LAP) and phenylalanine ammonia lyase (PAL) inhibitors. Results derived from ab initio calculations indicate that inhibitory activity is controlled by interactions with limited number of active site residues. Examination of entire hierarchy of theoretical models indicates that the inhibitory activity could be well represented by electrostatic interactions, leading to so called ‘‘electrostatic key-lock’’ principle
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References
L Pauling (1946) Molecular architecture and biological reactions, Chem Eng News 24, 1375–1377
L Pauling (1948) Chemical achievement and hope for the future, AmSci 36: 51–58
WL Jorgensen (2004) The many roles of computation in drugdiscovery, Science 303 (5665), 1813–1818
Ł Berlicki, P Kafarski (2005) Computer-Aided Analysis andDesign of Phosphonic and Phosphinic Enzyme Inhibitors as PotentialDrugs and Agrochemicals, Curr Org Chem 9 (18): 1829–1850
F Ooms (2000) Molecular Modeling and Computer Aided Drug DesignExamples of their Applications in Medicinal Chemistry, Curr MedChem 7: 141–158
I Muegge (2003) Selection criteria for drug-like compounds, MedRes Rev 23 (3): 302–321
R Abagyan, M Totrov (2001) High-throughput docking for leadgeneration, Curr Opin Chem Biol 5 (4): 375–382
KE Goodwill, MG Tennant, RC Stevens (2001) High-throughput x-raycrystallography for structure-based drug design, Drug DiscoveryToday 6 (2): 113–118
KH Gardner, LE Kay (1998) The use of H-2, C-13, N-15multidimensional NMR to study the structure and dynamics ofproteins, Ann Rev Biophys Biomol Struct 27: 357–406
V Kanelis, JD Forman-Kay, LE Kay (2001) Multidimensional NMRmethods for protein structure determination, IUBMB Life 52(6): 291–302
A Hillisch, LF Pineda, R Hilgenfeld (2004) Utility of homologymodels in the drug discovery process, Drug Discovery Today 9(15): 659–669
RD Taylor, PJ Jewsbury, JW Essex (2002) A review of protein-smallmolecule docking methods, J Comput Aided Mol Des 16 (3): 151–166
TJA Ewing, S Makino, AG Skillman, ID Kuntz (2001) DOCK 40: Searchstrategies for automated molecular docking of flexible moleculedatabases, J Comput Aided Mol Des 15 (5): 411–428
G Jones, P Willett, RC Glen (1995) Molecular recognition ofreceptor sites using a genetic algorithm with a description ofdesolvation, J Mol Biol 245 (1): 43–53
ML Verdonk, JC Cole, MJ Hartshorn, CW Murray, RD Taylor (2003) Improved Protein-Ligand Docking Using GOLD, Proteins 52(4): 609–623
M Rarey, B Kramer, T Lengauer, G Klebe (1996) A Fast FlexibleDocking Method using an Incremental Construction Algorithm, J MolBiol 261(3): 470–489
P Kirkpatrick (2004) Virtual screening: Gliding to success, NatureReviews Drug Discovery 3: 299–299
T A Halgren, R B Murphy, R A Friesner, H S Beard, L L Frye, W TPollard, J L Banks (2004) Glide: A New Approach for Rapid,Accurate Docking and Scoring 2 Enrichment Factors in DatabaseScreening, J Med Chem 47(7): 1750–1759
R A Friesner, J L Banks, R B Murphy, T A Halgren, J J Klicic, D TMainz, M P Repasky, E H Knoll, M Shelley, J K Perry, D E Shaw, PFrancis, P S Shenkin (2004) Glide: A New Approach for Rapid,Accurate Docking and Scoring 1 Method and Assessment of DockingAccuracy, J Med Chem 47(7): 1739–1749
H-J Böhm (1993) A novel computational tool for automatedstructure-based drug design, J Mol Rec 6(3): 131–137
G M Morris, DS Goodsell, RS Halliday, R Huey, WE Hart, RK Belew,AJ Olson (1998) Automated Docking Using a Lamarckian GeneticAlgorithm and Empirical Binding Free Energy Function, JComputChem 19: 1639–1662
H Gohlke, G Klebe, Approaches to the Description and Prediction ofthe Binding Affinity of Small-Molecule Ligands to MacromolecularReceptors, Angew Chem Int Ed 41(15): 2644–2676
hm1994 HJ Böhm (1994) The development of a simple empirical scoringfunction to estimate the binding constant for a protein-ligandcomplex of known three-dimensional structure, J Comput Aided Mol
MD Eldridge, CW Murray, TR Auton, GV Paolini, RP Mee (1997) Empirical scoring functions: I The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes, J Comput Aided Mol Des 11(5):425–445
G Jones, P Willett, RC Glen, AR Leach, R Taylor (1997) Development and Validation of a Genetic Algorithm for Flexible Docking, J Mol Biol 267(3):727–748
R Wang, L Lai, S Wang (2002) Further development and validation of empirical scoring functions for structure-based binding affinity prediction, J Comput Aided Mol Des 16(1):11–26
TJA Ewing, ID Kuntz (1997) Critical evaluation of search algorithms for automated molecular docking and database screening, J Comput Chem 18(9):1175–1189
H Gohlke, M Hendlich, G Klebe (2000) Knowledge-based scoring function to predict protein-ligand interactions, J Mol Biol 295(2):337–356
I Muegge, Y C Martin (1999) A General and Fast Scoring Function for Protein-Ligand Interactions: A Simplified Potential Approach, J Med Chem 42(5):791–804
P S Charifson, J J Corkery, M A Murcko, W P Walters (1999) Consensus Scoring: A Method for Obtaining Improved Hit Rates from Docking Databases of Three-Dimensional Structures into Proteins, J Med Chem 42(25):5100–5109
R Wang, Y Lu, S Wang (2003) Comparative Evaluation of 11 Scoring Functions for Molecular Docking, J Med Chem 46(12):2287–2303
M Jacobsson, P Liden, E Stjernschantz, H Bostrom, U Norinder (2003) Improving Structure-Based Virtual Screening by Multivariate Analysis of Scoring Data, J Med Chem 46(26):5781–5789
AC Anderson (2003) The Process of Structure-Based Drug Design, Chem Biol 10(9):787–797
RS Bohacek, C McMartin (1997) Modern computational chemistry and drug discovery: structure generating programs, Curr Opin Chem Biol 1(2):157–161
Y Nishibata, A Itai (1993) Confirmation of usefulness of a structure construction program based on three-dimensional receptor structure for rational lead generation, J Med Chem 36(20):2921–2928
RS Bohacek, C McMartin (1994) Multiple Highly Diverse Structures Complementary to Enzyme Binding Sites: Results of Extensive Application of a de Novo Design Method Incorporating Combinatorial Growth, J Am Chem Soc 116(13):5560–5571
SH Rotstein, MA Murcko (1993) GenStar: a method for de novo drug design, J Comput Aided Mol Des 7(1):23–43
DK Gehlhaar, KE Moerder, D Zichi, CJ Sherman, RC Ogden, ST Freer (1995) De novo design of enzyme inhibitors by Monte Carlo ligand generation, J Med Chem 38(3):466–472
V Gillet, AP Johnson, P Mata, S Sike, P Williams (1993) SPROUT: a program for structure generation, J Comput Aided Mol Des 7(2):127–153
DA Pearlman, MA Murcko (1993) CONCEPTS: New dynamic algorithm for de novo drug suggestion, J Comput Chem 14(10):1184–1193
JB Moon, WJ Howe (1991) Computer design of bioactive molecules: A method for receptor-based de novo ligand design, Proteins: Struct, Funct, Genet 11(4):314–328
V Tschinke, NC Cohen (1993) The NEWLEAD program: a new method for the design of candidate structures from pharmacophoric hypotheses, J Med Chem 36(24):3863–3870
SH Rotstein, MA Murcko (1993) GroupBuild: a fragment-based method for de novo drug design, J Med Chem 36(12):1700–1710
DC Roe, ID Kuntz (1993) BUILDER v2: improving the chemistry of a de novo design strategy, J Comput Aided Mol Des 9(3):269–282
MB Eisen, DC Wiley, M Karplus, RE Hubbard (1994) HOOK: A program for finding novel molecular architectures that satisfy the chemical and steric requirements of a macromolecule binding site, Proteins: Struct, Funct, Genet 19(3):199–221
DA Pearlman, MA Murcko (1996) CONCERTS: Dynamic Connection of Fragments as an Approach to de Novo Ligand Design, J Med Chem 39(8): 1651–1663
R S DeWitte, E I Shakhnovich (1996) SMoG: de Novo Design Method Based on Simple, Fast, and Accurate Free Energy Estimates 1 Methodology and Supporting Evidence, J Am Chem Soc 118(47): 11733–11744
R S DeWitte, A V Ishchenko, E I Shakhnovich (1997) SMoG: de Novo Design Method Based on Simple, Fast, and Accurate Free Energy Estimates 2 Case Studies in Molecular Design, J Am Chem Soc 119(20): 4608–4617
H-J Böhm (1992a) The computer program LUDI: a new method for the de novo design of enzyme inhibitors, J Comput Aided Mol Design 6(1): 61–78
H-J Böhm (1992b) LUDI: rule-based automatic design of new substituents for enzyme inhibitor leads, J Comput Aided Mol Design 6(6): 593–606
HJ Böhm (1996) Towards the automatic design of synthetically accessible protein ligands: peptides, amides and peptidomimetics, J Comput Aided Mol Design 10(4): 265–272
S F Boys, F Bernardi (1970) Calculation of small molecular interactions by differences of separate total energies – some procedures with reduced errors, Mol Phys 19(4): 553
WA Sokalski, S Roszak, K Pecul (1988) An efficient procedure for decomposition of the SCF interaction energy into components with reduced basis set dependence: Chem Phys Lett 153(2,3): 153–159
WA Sokalski, P Kedzierski, J Grembecka (2001) Ab initio study of the physical nature of interactions between enzyme active site fragments in vacuo, Phys Chem Chem Phys 3(5): 657–663
B Szefczyk, A J Mulholland, K E Ranaghan, W A Sokalski (2004) Differential transition-state stabilization in enzyme catalysis: quantum chemical analysis of interactions in the chorismate mutase reaction and prediction of the optimal catalytic field, J Am Chem Soc 126 (49): 16148–16159
J Grembecka, P Kedzierski, WA Sokalski (1999) Non-empirical analysis of the nature of the inhibitor-active-site interactions in leucine aminopeptidase, Chem Phys Lett 313(1): 385–392
J Grembecka, WA Sokalski, P Kafarski (2001) Quantum chemical analysis of the interactions of transition state analogs with leucine aminopeptidase, Int J Quantum Chem 84(2), 302–310
E Dyguda, J Grembecka, WA Sokalski, J Leszczynski (2005) Origins of the activity of PAL and LAP enzyme inhibitors: Toward ab initio binding affinity prediction, J Am Chem Soc 127(6): 1658–1659
A Taylor (1993) Aminopeptidases: towards a mechanism of action, Trends Biochem Sci 18: 167–171
EL Smith, RL Hill, (1960) in: The enzymes, Academic Press, New York, pp 37–62
N Strater, WN Lipscomb (1995) Two-metal ion mechanism of bovine lens leucine aminopeptidase: active site solvent structure and binding mode of L-leucinal, a gem-diolate transition state analogue, by X-ray crystallography, Biochemistry 34: 14792–14800
H Kim, WN Lipscomb (1994) Structure and mechanism of bovine lens leucine aminopeptidase, Adv Enzymol Relat Areas Mol Biol 68: 153–213
N Strater, L Sun, ER Kantrowitz, WN Lipscomb (1999) A bicarbonate ion as a general base in the mechanism of peptide hydrolysis by dizinc leucine aminopeptidase, Proc Natl Acad Sci USA 96: 11151–11155
A Taylor (1993) Aminopeptidases: structure and function, FASEB J 7: 290–298
H Umezawa (1980) Screening of small molecular microbial products modulating immune responses and bestatin, Recent Results Cancer Res 75: 115–125
SK Gupta, M Aziz, AA Khan (1989) Serum leucine aminopeptidase estimation: a sensitive prognostic indicator of invasiveness in breast carcinoma, Indian J Pathol Microbiol 32: 301–305
A Taylor, M Daims, J Lee, T Surgenor (1982) Identification and quantification of leucine aminopeptidase in aged normal and cataractous human lenses and ability of bovine lens LAP to cleave bovine crystallins, Curr Eye Res 2: 47–56
A Taylor, ,MJ Brown, ,MA Daims, ,J Cohen (1983) Localization of leucine aminopeptidase in normal hog lens by immunofluorescence and activity assays, Invest Ophthalmol Vis Sci 24:1172–1180
A Taylor, ,T Surgenor, ,DK Thomson, ,RJ Graham, ,H Oettgen (1984) Comparison of leucine aminopeptidase from human lens, beef lens and kidney, and hog lens and kidney, Exp Eye Res 38:217–229
CS Scott, ,M Davey, ,A Hamilton, ,DR Norfolk (1986) Serum enzyme concentrations in untreated acute myeloid leukaemia, Blut 52:297–303
J Beninga, ,KL Rock, ,AL Goldberg (1998) Interferon-gamma can stimulate post-proteasomal trimming of the N terminus of an antigenic peptide by inducing leucine aminopeptidase, J Biol Chem 273:18734–18742
G Pulido-Cejudo, ,B Conway, ,P Proulx, ,R Brown, ,CA Izaguirre (1997) Bestatin-mediated inhibition of leucine aminopeptidase may hinder HIV infection, Antiviral Res 36:167–177
J Grembecka, ,WA Sokalski, ,P Kafarski (2000) Computer-aided design and activity prediction of leucine aminopeptidase inhibitors, J Comput Aid Mol Des 14(6) 531–544
J Grembecka, ,A Mucha, ,T Cierpicki, ,P Kafarski (2003) The most potent organophosphorus inhibitors of leucine aminopeptidase Structure-based design, chemistry, and activity, J Med Chem 46(13):2641–2655
H-J Böhm (1998) Prediction of binding constants of protein ligands: A fast method for the prioritization of hits obtained from de novo design or 3D database search programs, J Comput Aided Mol Design 12(4):309–323
M Drag, ,J Grembecka, ,M Pawelczak, ,P Kafarski (2005) alpha-aminoalkylphosphonates as a tool in experimental optimisation of P1 side chain shape of potential inhibitors in S1 pocket of leucine - and neutral aminopeptidases, Eur J Med Chem 40(8):764–771
D Eisenberg, ,HS Gill, ,GM Pfluegl, ,SH Rotstein (2000) Structure-function relationships of glutamine synthetases, Biochim Biophys Acta 1477(1):122–145
ER Stadtman (2001) The Story of Glutamine Synthetase Regulation, J Biol Chem 276(48):44357–44364
GM Kishore, ,DM Shah (1988) Amino acid biosynthesis inhibitors as herbicides, Ann Rev Biochem 57:627–663
E Bayer, ,K H Gugel, ,K Hägele, ,H Hagenmaier, ,S Jessipow, ,W A Köonig, ,H Zähner (1972) Metabolic products of microorganisms 98 Phosphinothricin and phosphinothricyl-alanyl-analine, Helv Chim Acta 55:224–239
K Tachibana (1987) Herbicidal characteristics of bialphos, in Pesticide Science and Biotechnology, R Greenhalgh T.R. Roberts (Eds) pp 145–148
A Wild, ,H Sauer, ,W Rühle (1987) The effect of phosphinothricin (glufosinate) on photosynthesis I: Inhibition of photosynthesis and accumulation of ammonia, Z Naturforsch 42:263–269
K Tachibana, ,T Watanabe, ,Y Sekizawa, ,T Takematsu (1986) Accumulation of ammonia in plants treated with bialphos, J Pest Sci 11:33–37
PJ Lea, ,KW Joy, ,JL Ramos, ,MG Guerrero (1984) The action of 2-amino-4-(methylphosphinyl)-butanoic acid (phosphinothricin) and its 2-oxo-derivative on the metabolism of cyanobacteria and higher plants, Phytochemistry 23:1–6
A Wild, ,R Manderscheid (1984) The effect of phosphinothricin in the assimilation of ammonia in plants, Z Naturforsch 39:500–504
H Sauer, ,A Wild, ,W Rühle (1987) The effect of phosphinothricin (glufosinate) on photosynthesis II: The causes of inhibition of photosynthesis, Z Naturforsch 42:270–278
G Harth, ,MA Horwitz (1999) An inhibitor of exported Mycobacterium tuberculosis glutamine synthetase selectively blocks the growth of pathogenic mycobacteria in axenic culture and in human monocytes: extracellular proteins as potential novel drug targets, J Exp Med 189(9):1425–1436
G Harth, ,MA Horwitz (2003) Inhibition of Mycobacterium tuberculosis glutamine synthetase as a novel antibiotic strategy against tuberculosis: demonstration of efficacy in vivo, Infect Immun 71(1):456–464
RJ Almassy, CA Janson, R Hamlin, NH Xuong, D Eisenberg (1986) Novel subunit-subunit interactions in the structure of glutamine synthetase, Nature 323(6086):304–309
MM Yamashita, RJ Almassy, CA Janson, D Cascio, D Eisenberg (1989) Refined atomic model of glutamine synthetase at 35 A resolution, J Biol Chem 264:17681–17690
S H Liaw, D Eisenberg (1994) Structural model for the reaction mechanism of glutamine synthetase, based on five crystal structures of enzyme-substrate complexes, Biochemistry 33(3):675–681
RA Ronzio, A Meister (1968) Phosphorylation of Methionine Sulfoximine by Glutamine Synthetase, Proc Natl Acad Sci USA 59(1):164–170
J A Colanduoni, J J Villafranca (1986) Inhibition of E coli glutamine synthetase by phosphino -thricin, Bioorg Chem 14:163–169
H S Gill, D Eisenberg (2001) The Crystal Structure of Phosphinothricin in the Active Site of Glutamine Synthetase Illuminates the Mechanism of Enzymatic Inhibition, Biochemistry 40(7):1903–1912
L Berlicki, P Kafarski (2006), Computer-aided analysis of the interactions of glutamine synthetase with its inhibitors, Bioorg Med Chem 14(13):4578–4585
L Berlicki, A Obojska, G Forlani, P Kafarski (2005) Design, Synthesis, and Activity of Analogues of Phosphinothricin as Inhibitors of Glutamine Synthetase, J Med Chem 48(20):6340–6349
K RHanson, E A Havir (1981) Phenylalanine ammonia-lyase In The Biochemistry of Plants, Vol 7: Secondary Plant Metabolites Conn, E E edt; Academic Press, New York; pp 577–625
H Griesbach,H Lignins (1981) In The Biochemistry of Plants, Vol 7: Secondary Plant Metabolites Conn, E E edt; Academic Press, New York; pp 457–478
C N Sarkissian, Z Shao, F Blain, R Peevers, H S Su, R Heft, T M S Chang, T S Scriver (1999) A different approach to treatment of phenylketonuria: Phenylalanine degradation with recombinant phenylalanine ammonia lyase, Proc Natl Acad Sci USA 96(5):2339–2344
B Schuster, J Retey (1994) Serine-202 is the putative precursor of the active site dehydroalanine of phenylalanine ammonia lyase FEBS Lett 349(2):252–254
B Langer, D Rother, J Retey (1997) Identification of essential amino acids in phenylalanine ammonia-lyase by site-directed mutagenesis Biochemistry 36(36):10867–10871
M Baedeker, G E Schulz (2002) Structures of two histidine ammonia-lyase modifications and implications for the catalytic mechanism Eur J Biochem 269(6):1790–1797
T F Schwede, J Retey, G E Schulz (1999) Crystal structure of histidine ammonia-lyase revealing a novel polypeptide modification as the catalytic electrophile Biochemistry 38(17):5355–5361
D Rother, L Poppe, G Morlock, S Viergutz, J Retey (2002) An active site homology model of phenylalanine ammonia-lyase from Petroselinum crispum, Eur J Biochem 269(12):3065–3075
A Skolaut, J Retey (2001) 1,4-Dihydrophenylalanine – its synthesis and behavior in the phenylalanine ammonia-lyase reaction Archiv Biochem Biophys 393(2):187–191
J Zon, N Amrhein, R Gancarz (2002) Inhibitors of phenylalanine ammonia-lyase: 1-aminobenzylphosphonic acid substituted in the benzene ring Phytochemistry 59(1):9–21
C Appert, J Zoň, N Amrhein (2003) Kinetic analysis of the inhibition of phenylalanine ammonia-lyase by 2-aminoindan-2-phosphonic acid and other phenylalanine analogues Phytochemistry 62(3):415–422
J Zoň, P Miziak, N Amrhein, R Gancarz (2005) Inhibitors of Phenylanine Ammonia-Lyase (PAL): Synthesis and Biological Evaluation of 5-Substituted 2-Aminoindane-2-phosphonic Acids Chemistry and Biodiversity 2(9):1187–1194
H Ritter, G E Schulz (2004) Structural Basis for the Entrance into the Phenylpropanoid Metabolism Catalyzed by Phenylalanine Ammonia-Lyase The Plant Cell 16(12):3426-3436
J C Calabrese, D B Jordan, A Boodhoo, S Sariaslani, T Vannelli (2004) Crystal Structure of Phenylalanine Ammonia-Lyase: Multiple Helix Dipoles Implicated in Catalysis. Biochemistry 43(36):11403–11416
B Langer, M Langer, J Retey (2001) Methylidene-imidazolone (MIO) from histidine and phenylalanine ammonia-lyase, Adv Protein Chem 58:175–214
L Maier, P J Diel (1994) Synthesis, physical and biological properties of the phosphorus analogs of phenylalanine and related compounds, Phosphorus Sulfur 90(1–4):259–279
L E Chirlian, M M Francl (1987) Atomic charges derived from electrostatic potentials – a detailed study, J Comp Chem 8(6):894–905
G Naray-Szabo (1984) Quantum chemical calculation of the enzyme ligand interaction energy for trypsin inhibition by benzamidines, J Am Chem Soc 106(16):4584–4589
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Berlicki, Ł., Grembecka, J., Dyguda-Kazimierowicz, E., Kafarski, P., Sokalski, W.A. (2007). From Inhibitors of Lap to Inhibitors of Pal. In: Sokalski, W.A. (eds) Molecular Materials with Specific Interactions – Modeling and Design. Challenges and Advances in Computational Chemistry and Physics, vol 4. Springer, Dordrecht. https://doi.org/10.1007/1-4020-5372-X_8
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