Synthesis and biological investigation of pyrimido 1,2 a 1,3,5 triazine and its analogues 2

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Synthesis and biological investigation of pyrimido 1,2 a 1,3,5 triazine and its analogues 2

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Table XVIII Retrieval of top targets of 149b by approaches: Pharm S.No Target name Function PDB ids Mapper (fit Reverse Screen 3d score score) Epidermal growth factor receptor Heat shock protein HSP 90-alpha 144 Cathepsin K Purine nucleoside phosphorylase Cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands 3lzb, 2qlq 3.751 0.4365 2xdx,1uyk, 1uyh,1uy6, 1uyg 3.749 0.5652 Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling 1tu6, 3kx1 3.593 0.5714 Nucleotide transport and metabolism 1a9t, 1lv8, 1pr4, 1ovg, 1vmk, 2qpl, 1z36, 1rfg, 1k9s, 3iom, 3.473 0.9375 Molecular chaperone Has ATPase activity (By similarity) 1odj Leukotriene A-4 hydrolase Hydrolyzes an epoxide moiety of leukotriene A4 (LTA-4) to form leukotriene B4 (LTB-4) 1gw6, 3fum 3.413 0.4483 Corticosteroid 11-betadehydrogenase isozyme Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone 3czr, 3czr, 3d5q 3.205 0.4412 Aspartate aminotransferase Amino acid transport and metabolism 1c9c, 2z9v, 3.131 0.6842 Nucleotide transport and metabolism 1tls,1j3j, 1tlc, 3jsu, 2blc, 3clb, 3k2h, 2aaz, 1sej, 1ju6, 1qzf, 1f28, 1jtq, 1f4d, 3.131 0.5 3.041 0.4667 Thymidylate synthase Mitogen-activated protein kinase 14 Involved in MAP kinase activity 3e92, 3fc1, 1ouy,3new, 3fl4, 1w82 10 Proto-oncogene tyrosineprotein kinase Src implicated in the pathogenesis of chronic myelogenous leukemia 1o4r, 2h8h, 3g6g, 3f3t, 1o4i, 1o47 3.024 0.4324 Androgen receptor Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation 1z95, 2ax8, 2piq, 3b66 2.994 0.281 11 145 12 Dihydroorotate dehydrogenase, mitochondrial Nucleotide transport and metabolism 2fpy, 1d3h, 2prl, 1tv5, 3i6r 3.405 0.5 13 Cell division protein kinase Involved in protein kinase activity 1p2a, 3eoc, 2v22, 1vop 2.979 0.36111 14 Serine/threonine-protein kinase Chk1 Required for checkpoint mediated cell cycle arrest in response to DNA damage or the presence of unreplicated DNA May also negatively regulate cell cycle progression Recognizes the substrate consensus sequence [RX-X- S/T] 2ayp, 2e9p, 2e9u, 2.969 0.4375 15 Enoyl-[acyl-carrierprotein] reductase [NADH] Lipid transport and metabolism 1bvr, 1d8a, 3fng, 1jvf, 3fne 2.963 0.3871 1nhu, 2f9v, 1yvx, 1nhv, 2a4g, 2pxa 2.942 0.3333 16 - 17 Tyrosine-protein phosphatase non-receptor type May play an important role in CKII- and p60csrc-induced signal transduction cascades 1no6, 1nny, 3o5x, 1c85, 2shp 2.936 0.2917 18 146 HCV RNA polymerase Dipeptidyl peptidase Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N- 1rwq, 2gbi, 2iit, 1rwq, 2.931 0.5667 termini provided that the penultimate residue is proline Plays a role in T-cell activation 2aj8 19 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase phosphorus-oxygen lyase participates in biosynthesis of steroids 1h48, 3ke1 2.927 0.3636 20 Retinoic acid receptor RXR-beta Nuclear hormone receptor Involved in the retinoic acid response pathway Binds 9-cis retinoic acid (9C-RA) 1h9u 2.923 0.4687 Phospholipase A2 KPA2 Involved in phospholipase A2 activity which cleaves glycerophospholipids to release fatty acids and lysophospholipids 1po8, 1db5, 1fv0, 1rgb, 1qll, 1oxr, 3l30, 3fo7, 3l69, 2.932 0.65 22 E3 ubiquitin-protein ligase Mdm2 MDM2, a p53-specific E3 ubiquitin ligase, is the principal cellular antagonist of p53, acting to limit the p53 growth-suppressive function in unstressed cells 1ttv 2.918 0.4166 23 Collagenase Degrades collagen type I Does not act on gelatin or casein Could have a role in tumoral process 1xud, 3kek 2.916 0.359 24 Macrophage metalloelastase Human Macrophage Metalloelastase Correlates with Angiogenesis and Prognosis of Gastric Carcinoma 1ros 2.915 0.375 21 147 25 3-hydroxy-3methylglutaryl-coenzyme A reductase This transmembrane glycoprotein is the ratelimiting enzyme of sterol biosynthesis 2q1l, 3cd0, 3cd7, 3cd5, 3cct 2.979 0.3 26 Probable uracil phosphoribosyltransferase Nucleotide transport and metabolism 1xtu, 1vst 2.895 0.333 27 2-amino-4-hydroxy-6hydroxymethyldihydropteri dine pyrophosphokinase Coenzyme transport and metabolism 1q0n, 3ip0 2.892 0.619 28 Matrix metalloproteinase-9 May play an essential role in local proteolysis of the extracellular matrix and in leukocyte migration 1gkd, 2ovx, 2ozr 2.879 0.35 29 3-oxoacyl-[acyl-carrierprotein] synthase Lipid transport and metabolism 1u6s, 3il6 2.877 0.325 Involved in RNA binding, 2gpq, 2idv, 1ap8, 2wmc, 1ipb, 1wkw, 3hxg 2.855 0.4412 2.852 0.3409 30 Eukaryotic translation initiation factor 4E Phosphorylates and activates not only 148 3-phosphoinositidedependent protein kinase PKB/AKT, but also PKA, PKC-zeta, RPS6KA1 3nax, 2v4l, and RPS6KB1 May play a general role in 3oaw, 3ml8, signaling processes and in development 31 1uu3, 2xck, 3dpd, 3ml9 1e7v, 2chz, 2chx, 2chw, 1e8x, 3ls8 32 Signal recognition particle protein Intracellular trafficking, secretion, and vesicular transport 1o87, 2c03 2.851 0.3714 33 Scytalone dehydratase Involved in hydro-lyase activity 7std, 6std, 5std 3.835 0.5 34 Pantothenate synthetase Coenzyme transport and metabolism 1n2h, 3ivc 3.106 0.4571 35 UDP-glucose 4-epimerase Cell wall/membrane/envelope biogenesis 1lrj, 1lrl, 1ek6 2.98 0.2885 36 Nicotinate-nucleotidedimethylbenzimidazolepho sphoribosyltransferase - 1l5l, 1l5m 2.966 0.888 2.992 0.491 2.908 0.5517 Motor protein required for establishing a bipolar 37 Kinesin like protein kif11 spindle Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis 38 Lactoylglutathione lyase Catalyzes the conversion of hemimercaptal, formed from methylglyoxal and glutathione, to 149 3k5e, 2gm1, 2uym, 3cjo 1fro, 2za0 S-lactoylglutathione Hepatocyte growth factor receptor Involved in hepatocyte growth factor activity 3cd8, 3c1x 2.901 0.3478 Transthyretin Thyroid hormone-binding protein Probably transports thyroxine from the bloodstream to the brain 1rlb, 2f8i, 3ng5, 3ipe 2.893 0.5357 41 TGF-beta receptor type-1 On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases It then bind and activate SMAD transcriptional complex, enters the nucleus where it binds transcription cofactors and causes the transcription of DNA 1rw8, 2wot 2.879 0.3902 42 Methionine aminopeptidase Translation, ribosomal structure and biogenesis 2ea2, 1boa, 2gg8, 2p98, 2g6p 2.948 0.5862 43 1-aminocyclopropane-1carboxylate deaminase Amino acid transport and metabolism 1j0e, 1j0b 2.867 0.5 44 Cell division protein kinase Involved in protein kinase activity 2vtp, 3eoc 2.853 0.4444 39 40 150 Table XIX Retrieval of top targets of 149f by different VS approaches Pharm S No Protein name (target name) Function PDB ids Reverse Mapper (fit Screen 3d score) score 1s59, 1mn9 3.907 0.2703 1lv8, 1ovg, 1rfg, 1odj, 3iom, 2ai1 4.23 0.52 3.569 0.3429 3.397 0.2917 enzymes that catalyze the exchange of Nucleoside diphosphate kinase phosphate groups between different nucleoside diphosphates Purine nucleoside phosphorylase Nucleotide transport and metabolism Phosphoenolpyruvate carboxykinase, cytosolic [GTP] Energy production and conversion 1m51, 1nhx 1khb 1lrj, 1hzj UDP-glucose 4-epimerase Cell wall/membrane/envelope biogenesis 2p5y, 2c20, 3ehe, 3enk 151 Hypothetical protein - 1vhn, 2q6i, 3kyf, 3kyg, 1ofu, 2e87, 2yqz, 2hek, 2ogi, 1yre, 2d1y, 1p0h, 1q6y, 2gf6 3.358 0.2799 3.197 0.2906 1emd, 3i0p, 1emd, 1hex, 1o6z, 1ur5, 3gvh, 1b8v, 1bmd, 1z2i, 2dfd, 2x0i, 1guz, 1gv0 3.141 0.2653 1jmf, 1tlc, 1b02 3.132 0.522 3.082 0.6163 1nqu, 2c9b, 6,7-dimethyl-8ribityllumazine synthase Coenzyme transport and metabolism 1t13, 2f59, 2obx, 1nqu, 1kyy Thymidylate synthase Nucleotide transport and metabolism 152 Malate dehydrogenase enzyme in the citric acid cycle that catalyzes the conversion of malate into oxaloacetate Imidazole glycerol phosphate synthase 1ox6, 1ox5 - This transmembrane glycoprotein is involved in the control of cholesterol biosynthesis It is the rate-limiting enzyme of sterol biosynthesis 10 3-hydroxy-3-methylglutarylcoenzyme A reductase Heat shock protein HSP 90alpha Molecular chaperone Has ATPase 11 Cell division protein kinase Involved in protein kinase activity 12 activity (By similarity) 2q1l, 3cd7, 3ccw, 1qax, 3cd5, 1dqa, 1r31 2.991 0.2991 1uyg, 3hz5 2.989 0.3737 2.97 0.4242 2.963 0.4938 2.959 0.3288 2.932 0.3871 1p2a, lke9, 2bts, 2wih 1jvf, 1d8a, 13 Enoyl-[acyl-carrier-protein] reductase [NADH] Lipid transport and metabolism 3gr6, 3oig, 1qsg, 2h7i, 2h9i, 2pd4 Has a tyrosine-protein kinase activity The VEGF-kinase ligand/receptor signaling 14 Vascular endothelial growth factor receptor system plays a key role in vascular development and regulation of vascular 2oh4, 1ywn, 3c7q, 3c7q permeability 15 153 2-C-methyl-D-erythritol 2,4cyclodiphosphate synthase - 1h48, 3ke1, phosphorylase 16 17 18 19 20 184 1i80, 3lba, 1odj, 1z39, 2p4s, 3of3, 1oty May play an important role in CKII- and p60c-src-induced signal transduction cascades (By similarity) 1jf7, 1ecv, 1no6, 1c83, 3o5x 3.285 0.28 Cell division protein kinase Involved in protein kinase activity 2bts, 2vtj, 2b52, 2vti, 1gih, 3bhv 2.983 0.41 Cathepsin S Thiol protease Key protease responsible for the removal of the invariant chain from MHC class II molecules 1nqc, 3n3g, 3mpf 2.97 0.29 Dipeptidyl peptidase Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline Plays a role in T-cell activation 2g5t, 2aj8, 2gbi, 1rwq 2.962 0.32 Streptavidin The biological function of streptavidin is not known Forms a strong non-covalent specific complex with biotin (one molecule of biotin per subunit of streptavidin) 1sre, 1srj 2.959 0.32 Tyrosine-protein phosphatase non-receptor type 21 Nucleotide transport and metabolism 2fpy, 1uuo, 1d3g 2.959 0.31 22 Hepatocyte growth factor receptor Involved in hepatocyte growth factor activity 3f82, 3cd8 2.956 0.27 23 Branched-chain-amino-acid aminotransferase, mitochondrial Amino acid transport and metabolism 1kta, 1kt8 2.94 0.26 24 Renin Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney 1bil, 2v12, 2glo 2.932 0.28 25 Bile acid receptor - 3okh, 3oki, 1ot7 2.929 0.34 26 Corticosteroid 11-betadehydrogenase isozyme Catalyzes reversibly the conversion of cortisol to the inactive metabolite cortisone Catalyzes reversibly the conversion of 7-ketocholesterol to 7-betahydroxycholesterol 3ch6 2.928 0.31 27 185 Dihydroorotate dehydrogenase, mitochondrial Glycogen synthase kinase-3 Participates in the Wnt signaling pathway Implicated in the hormonal control of 1q4l, 1q3d, 2.925 0.31 beta 28 Heat shock protein HSP 90alpha Molecular chaperone Has ATPase activity (By similarity) 1osf, 2xdx 2.914 0.34 29 Casein kinase II subunit alpha Involved in protein kinase activity 1om1, 1oml, 3owl 2.901 0.39 30 Guanine nucleotide-binding protein G(i), alpha-1 subunit Involved in signal transducer activity 1svk, 2ode 2.9 0.24 31 Proto-oncogene serine/threonine-protein kinase Pim-1 Involved in protein kinase activity 3bgz 2.894 0.31 32 Neutrophil gelatinaseassociated lipocalin Transport of small lipophilic substances (Potential) 1x8u, 3hwf 3.2 0.31 33 Probable uracil phosphoribosyltransferase Nucleotide transport and metabolism 1xtu, 1vst, 3.129 0.33 34 Leukotriene A-4 hydrolase Hydrolyzes an epoxide moiety of leukotriene A4 (LTA-4) to form leukotriene B4 (LTB-4) The enzyme also has some peptidase activity 1gw6, 3ftz 3.013 0.5 35 186 several regulatory proteins including glycogen synthase, MYB and the transcription factor JUN 3f88 Androgen receptor Steroid hormone receptors are ligandactivated transcription factors that regulate 3b68, 2piq, 2.988 0.64 eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues 1gs4 36 Involved in DNA binding 3dy6, 1y0s 2.982 0.34 37 Tyrosine-protein phosphatase non-receptor type May play an important role in CKII- and p60c-src-induced signal transduction cascades (By similarity) 1onz, 1no6, 1jf7, 3o5x, 1q6t 2.974 0.35 38 3-hydroxy-3-methylglutarylcoenzyme A reductase This transmembrane glycoprotein is involved in the control of cholesterol biosynthesis It is the rate-limiting enzyme of sterol biosynthesis 3cd7, 3cd5, 2q1l, 1hwk, 2r4f, 3cct 2.961 0.32 39 Seminal ribonuclease Involved in nucleic acid binding 1tq9, 11bg 2.959 0.43 40 Scytalone dehydratase Involved in hydro-lyase activity 7std, 5std 2.958 0.275 41 Inositol-3-phosphate synthase Lipid transport and metabolism 1rm0, 1p1j 2.946 0.31 42 Tyrosine-protein phosphatase non-receptor type May play an important role in CKII- and p60c-src-induced signal transduction cascades (By similarity) 1q6t, 3o5x, 1jf7, 1no6, 1onz 2.974 0.35 43 187 Peroxisome proliferatoractivated receptor delta Histone deacetylase Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) Histone 1t67, 2v5x 2.929 0.3 deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation 44 Enoyl-[acyl-carrier-protein] reductase [NADH] Lipid transport and metabolism 1d8a, 3fne 2.92 0.47 45 4-hydroxyphenylpyruvate dioxygenase Amino acid transport and metabolism 1sqi, 1tfz 2.919 0.38 46 Caspase-3 Involved in the activation cascade of caspases responsible for apoptosis execution 1nms, 3dej 2.919 0.44 47 Phospholipase A2 VRV-PLVIIIa Involved in phospholipase A2 activity 1q7a, 3fo7, 1fv0 2.916 0.69 48 Transthyretin Thyroid hormone-binding protein Probably transports thyroxine from the bloodstream to the brain 1dvu, 2qgc, 3ng5, 3ipe 2.913 0.68 49 Isocitrate dehydrogenase [NADP] Energy production and conversion 1hj6, 2qfx, 3inm 2.913 0.26 Vascular endothelial growth factor receptor Has a tyrosine-protein kinase activity The VEGF-kinase ligand/receptor signaling system plays a key role in vascular development and regulation of vascular 3c7q, 1ywn, 1y6a, 3ewh 2.898 0.38 50 188 permeability T-cell ecto-ADPribosyltransferase Involved in NAD(P)+-protein-arginine ADP-ribosyltransferase activity Kinesin-like protein KIF11 Motor protein required for establishing a bipolar spindle Blocking of KIF11 prevents centrosome migration and arrest cells in mitosis with monoastral microtubule arrays 51 52 1gxz, 1og4 2.896 0.31 2.924 0.41 3k5e, 2gm1, 2uym, 3cjo, 2fme Table XXIV Retrieval of predicted targets implicated in cancer for the six selected synthesized compounds by using INVDOCK with their scores ELP (Ligand protein interaction energy in Kcal/mol) Targets Function 149b 149f 173b 173c 173f 173h Tyrosine-protein kinase JAK2 Involved in interleukin3 signal transduction -39.1 - - -49 -43.3 -41.6 Rxr retinoid x receptor Nuclear hormone receptor Involved in the retinoic acid response pathway Binds 9-cis retinoic acid (9C-RA) -46.7 -44.8 -51.2 -43.2 -43.2 -45.3 human mitotic kinesin eg5 (ksp) Motor protein required for establishing a bipolar spindle -42.1 - - - - -47.7 189 Her-2 (erbb-2) HER2 is a cell membrane surface-bound receptor tyrosine kinase involved in the signal transduction pathways leading to cell growth and differentiation -44.5 -50.5 -44.3 -49.4 -51.8 -52.7 Thymidylate synthase Enzyme used to generate thymidine monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis -43 -42.8 -41.7 -46 -44.3 -44.3 Map kinase p38 p38 mitogen-activated protein kinases are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat and osmotic shock, and are involved in cell differentiation and apoptosis -41.2 -47.1 -41.8 -42.3 -46 -43.3 -40.1 -43.6 -44.3 -50.5 -45.2 -42.4 -41.2 -43.2 -42.8 -41.2 -43.9 -43.8 Epidermal growth factor receptor Phosphatidylinosi tol 3-kinase ca/p110 Cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands PI3Ks are a family of related intracellular signal transducer enzymes capable of phosphorylating the position hydroxyl group of the inositol ring of phosphatidylinositol Bifunctional dihydrofolate reductase -40.1 -42 -43 -48.8 -50.6 -46.6 Transforming protein p21/ human Ras 190 Coenzyme transport and metabolism Essential component of signal transduction pathways that regulate cell growth, proliferation, differentiation, and apoptosis -40.4 - -51.2 -57.6 -46.4 -52.5 bcr-abl tyrosine kinase Philadelphia chromosome leads to a fusion protein of abl (Abelson proto-oncogene) with bcr (breakpoint cluster region), termed bcr-abl This is now a constitutively active tyrosine kinase, implicated in the pathogenesis of chronic myelogenous leukemia -40.4 - -41.4 -48.7 -44 -43.4 CDK2 Involved in protein kinase activity -41.8 -41.4 - - - -43.1 Chk1 Abrogating the G2 DNA damage checkpoint - - - - - -42 Hsp90 Molecular chaperone which is upregulated in response to stress - - - - - -43.2 Target was not retrieved (“-”) 191 Table XXV Validation of predicted cancer targets based on ligand similarity, structures of their substrates/inhibitors and Tanimoto scores Tanimoto (Pdb id) substrates/inhibitors Tanimoto Tanimoto Tanimoto Tanimoto Score score Score Score Score Score (149f) (173b) (173c) (173f) (173h) - Structures of their Tanimoto (149b) Targets - - - - - - - - - - - N O N Tyrosineprotein kinase \2 (2b7a)164 O O O S O NH H3C RXR Retinoid X receptor (1mzn)165 CH3 H3C CH3 CH2 CH3 Bexarotene 192 COOH O O N N CH3 N 0.5362 - - - - 0.5571 - NH2 - - - 0.5263 0.5179 - - - - - - Cl OH O human mitotic kinesin Eg5/ KSP (2fme)166,167 N OH O O NH N H S Monastrol Her-2/ErbB-2 (1n8z)168 H3C O S O O NH HN O Cl N N Lapatinib 193 F N O thymidylate synthase (1f28)169 S CH3 HN - 0.5667 H2N 0.5833 0.5714 0.5775 0.56 0.6102 0.5932 0.5385 0.5313 N Nolatrexed (thymitaq) O H N N 0.6034 0.5468 0.5645 0.6 0.5857 0.6027 0.5753 N N H2C 0.5932 N N NH MAP kinase p38 (1bmk)170 H N O N Me N O Me N HN 194 O Me O HO - 0.5811 0.5556 0.5417 0.5811 0.5909 0.6290 0.6308 0.6833 0.6667 0.6563 0.6774 - Me - HN Me N OH N N Me O NH2 O N N N O NH NH F3C Cl Me epidermal growth factor receptor (1m17)171 195 O O N N O HN Me O C CH - - 0.5224 - Erlotinib NH2 N N phosphatidyli nositol 3kinase CA/p110 (1okz)172 0.65 0.625 0.7368 0.7193 0.6508 0.6452 0.6308 N 0.6324 0.5821 0.5672 0.5634 0.5571 0.5968 0.5758 0.6780 0.6610 0.6508 0.6190 0.614 0.5902 0.7037 0.6852 0.6167 0.6102 N N Me N Me O O Me H N N N N O Me O H N Ph NBn O Bifunctional dihydrofolate reductase (1j3j)173 196 SMe Me Me Me HN N H2N Transforming protein N N Me N - P21/H-RAS-1 (1nvv) Cl HN Bcr-Abl tyrosine kinase (2h8h)174-176 N H N N Me O - 0.7258 0.7097 0.6716 0.6418 - - 0.6923 0.6769 0.6912 0.6866 - - - - 0.5441 - Cl 0.7258 - R - - - - 0.5410 R = SCH3 Cl HN R N H N N Me O Cl R = CH2OH O N H2N CDK2 N 177 (2bts) N H2N N O N CHK1 (3qyk)178 N F 197 O NH2 N HSP90 (2ayp)179 NH HN Cl N N H - - O *The cut off for TC was 0.5 and the values below 0.5 are not shown 198 0.5143 ... Methionine aminopeptidase Translation, ribosomal structure and biogenesis 2ea2, 1boa, 2gg8, 2p98, 2g6p 2. 948 0.58 62 43 1-aminocyclopropane-1carboxylate deaminase Amino acid transport and metabolism... hepatocyte growth factor activity 3f 82, 3cd8 2. 956 0 .27 23 Branched-chain-amino-acid aminotransferase, mitochondrial Amino acid transport and metabolism 1kta, 1kt8 2. 94 0 .26 24 Renin Renin is a. .. Met- and Leu-enkephalins by cleavage of a Gly-Phe bond 1r1i, 1y8j 3 .29 8 0.3548 3.644 0 .22 58 17 20 21 Amino acid transport and metabolism 22 DNA polymerase I, thermostable Replication, recombination

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