COMPOUNDS WEAKENING SAICAR SYNTHETASE ACTIVITY AND APPLICATIONS

Abstract

Provided are compounds reducing SAICAR accumulation, and applications. On the basis of existing protein structure data and small molecule structure data, calculations and analysis are performed using software to screen and obtain compounds capable of effectively interfering with PAICS activity, reducing SAICAR synthesis, and ultimately reducing SAICAR accumulation, in order to achieve the goal of treating or improving ADSL deficiency. A better effect in the treatment or improvement of ADSL deficiency is expected from the joint use of at least two of the described compounds.

Claims

1. A method for treating or alleviating a disease caused by excessive accumulation of SAICAR, comprising the administration of a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof to a patient, wherein the compound is selected from compounds with DrugBank IDs DB03639, DB01821, DB04700, DB02927, DB02267, DB04633, DB04207, DB03433, DB03003, DB01910, DB01813, DB02011, DB03327, DB02075, DB02077, DB01815, DB01974, DB04323, DB03927, DB03582, DB02537, DB01634, DB04153, DB04649, DB04778, DB02824, DB04701, DB01657, DB02941, DB04684, DB02492, DB03427, DB03686, DB04762, DB03602, DB03566, DB04808, DB04341, DB01895, DB03624, DB04434, and DB04602.

2. The method according to claim 1, wherein the SAICAR is synthesized by an enzyme PAICS.

3. The method according to claim 1, wherein the pharmaceutically acceptable derivative of the compound is a simple derivative thereof.

4. The method according to claim 3, wherein the simple derivative is one of lower ester, lower ether, lower alkyl substituent, pharmaceutical salt and lower amide of the compound.

5-7. (canceled)

8. A composition for treating or alleviating a disease caused by excessive accumulation of SAICAR or a disease which can be alleviated by inhibiting PAICS activity, comprising an active ingredient which comprises at least one selected from compounds with DrugBank IDs DB03639, DB01821, DB04700, DB02927, DB02267, DB04633, DB04207, DB03433, DB03003, DB01910, DB01813, DB02011, DB03327, DB02075, DB02077, DB01815, DB01974, DB04323, DB03927, DB03582, DB02537, DB01634, DB04153, DB04649, DB04778, DB02824, DB04701, DB01657, DB02941, DB04684, DB02492, DB03427, DB03686, DB04762, DB03602, DB03566, DB04808, DB04341, DB01895, DB03624, DB04434 and DB04602, or pharmaceutically acceptable derivatives thereof.

9. The composition according to claim 8, wherein the active ingredient comprises at least two selected from compounds with DrugBank IDs DB03639, DB01821, DB04700, DB02927, DB02267, DB04633, DB04207, DB03433, DB03003, DB01910, DB01813, DB02011, DB03327, DB02075, DB02077, DB01815, DB01974, DB04323, DB03927, DB03582, DB02537, DB01634, DB04153, DB04649, DB04778, DB02824, DB04701, DB01657, DB02941, DB04684, DB02492, DB03427, DB03686, DB04762, DB03602, DB03566, DB04808, DB04341, DB01895, DB03624, DB04434 and DB04602, or pharmaceutically acceptable derivatives thereof.

10. The composition according to claim 8, wherein the pharmaceutically acceptable derivative of the compound is a simple derivative thereof.

11. The composition according to claim 10, wherein the simple derivative is one of lower ester, lower ether, lower alkyl substituent, pharmaceutical salt, and lower amide of the compound.

12. The composition according to any one of claim 8, further comprising a pharmaceutically or bromatologically acceptable adjuvant.

13-15. (canceled)

16. The method according to claim 1, wherein the disease caused by the excessive accumulation of SAICAR comprises ADSL deficiency.

17. A method for treating a disease which can be alleviated by inhibiting PAICS activity, comprising the administration of a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof to a patient, wherein the compound is selected from compounds with DrugBank IDs DB03639, DB01821, DB04700, DB02927, DB02267, DB04633, DB04207, DB03433, DB03003, DB01910, DB01813, DB02011, DB03327, DB02075, DB02077, DB01815, DB01974, DB04323, DB03927, DB03582, DB02537, DB01634, DB04153, DB04649, DB04778, DB02824, DB04701, DB01657, DB02941, DB04684, DB02492, DB03427, DB03686, DB04762, DB03602, DB03566, DB04808, DB04341, DB01895, DB03624, DB04434, and DB04602.

18. The method according to claim 17, wherein the pharmaceutically acceptable derivative of the compound is a simple derivative thereof.

19. The method according to claim 18, wherein the simple derivative is one of lower ester, lower ether, lower alkyl substituent, pharmaceutical salt and lower amide of the compound.

20. The method according to claim 17, wherein the disease which can be alleviated by inhibiting PAICS activity, comprises a tumor with high expression of PAICS.

21. The composition according to claim 8, wherein the disease caused by the excessive accumulation of SAICAR comprises ADSL deficiency.

22. The composition according to claim 8, wherein the disease which can be alleviated by inhibiting PAICS activity, comprises a tumor with high expression of PAICS.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1 shows a 3D solid ribbon structure diagram of PAICS;

[0016] FIG. 2 shows diagrams indicating the interaction of CAIR and SAICAR synthetase in the crystal structure, in which A: PDB access ID 2GQS; B: PDB access ID 2CNQ; and C: PDB access ID 4FE2; and

[0017] FIG. 3 shows the alignment result of different types of SAICAR synthetase protein sequences.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0018] There are 425 amino acid residues in full length of the human PAICS protein sequence, in which a fragment of 2-260 AA is a SAICAR synthetase domain, and a fragment of 267-425AA is an AIR carboxylase domain, these two domains are linked by a 6-peptide (KSESQC). Furthermore, GLN159-GLN183 -helix in the SAICAR synthetase domain interacts with ASN395-ASN424 -helix in the AIR carboxylase domain, and tightly bind together, as shown in FIG. 1.

[0019] A protein structure data bank (RCSB) collects the crystal structure data of SAICAR synthetases of different origins, which include Saccharomyces cerevisiae (1A48, 2CNQ, 2CNV, 2CNU, 1OBD, 1OBG), Pyrococcushorikoshii OT3 (3U54, 3U55), Escherichia coli (2GQR, 2GQS), Methanocaldococcusjannaschii (2YZL, 2Z02), Streptococcus pneumonia (4FGR, 4FE2), Mycobacterium abscessus ATCC 19977/DSM 44196 (3R9R), Thermotoga maritime (1KUT), Clostridium perfringens (3NUA), Ehrlichiachaffeensis (3KRE), Geobacilluskaustophilus (2YWV) as well as PAICS crystal structure data Homo sapiens (2H31) and Bombyxmori (4JA0). Wherein, there are complexes 2GQS, 2CNQ and 4FE2 which contain the structure of CAIR, and complexes 2CNV, 2CNU and 4FE2 which contain the structure of ASP.

[0020] As shown in FIG. 2, the residues within CAIR 3A in 2CNQ are Arg122, Ser128, ASP215, Arg242 and Arg264; the residues within CAIR 3A in 2GQS are Arg94, Ser100, ASP129, ASP175, Arg199 and Arg215; the residues within CAIR 3A in 4FE2 are Arg93, Ser99, ASP174, Arg199, and Arg214. With reference to the alignment result of the SAICAR protein sequences of different species (FIG. 3), it can be seen that the binding sequences of SAICAR synthetases of different species with CAIR exhibits high-level conservative, and CAIR is primarily fixed by hydrogen bonds.

[0021] On the basis of the above results, the crystal structure conformations in SAICAR synthetases of Saccharormyces cerevisiae (PDB: 2CNQ) and Escherichia coli (PDB: 2GQS) are used as receptor structures for calculating and screening, since there is no conformation which can bind CAIR in human PAICS crystal structure, and no catalytic conformation formed in the catalytic region, and the results obtained by calculation are not reliable. 4661 of small molecule drugs in the DrugBank (http://www.drugbank.ca/downloads#structures) are calculated and screened by using the ligand fit module of Discovery studio. The conformations are ordered according to dock scores, and then the first 500 conformations are selected. After eliminating the repetitions, key screening results are obtained. In addition, the inhibition ratios of the compounds against SAICAR accumulation are confirmed by biochemical enzyme activity experiments and cell biology experiments, as shown in Table 1.

TABLE-US-00001 TABLE 1 Calculating-Screening Results and SAICAR Inhibition Ratio Results SAICAR synthetase of Escherichia coli Inhibition ratios against DrugBank Dock SAICAR No. ID Common name Score accumulation 1 DB03639 1-Guanidinium-7-Aminoheptane 365.651 79.185% 2 DB01821 L-N(Omega)-Nitroarginine-2,4-L- 279.201 57.11% Diaminobutyric Amide 3 DB04700 GLUTATHIONE SULFINATE 276.972 9.98% 4 DB02927 Mixed Carbamic Phosphoric Acid 272.952 22.8% Anhydride of 7,8-Diaminononanic acid 5 DB02267 Argininosuccinate 268.699 86.81% 6 DB04633 N-ethyl-N[3-(propylamino)propyl]propane-1,3- 262.124 12.798% diamine 7 DB04207 N-(5-Amino-5-Carboxypentyl)-Glutamic Acid 261.457 65.69% 8 DB03433 {[(3-Hydroxy-2-Methyl-5-Phosphonooxymethyl- 261.442 53.38% Pyridin-4-ylmethyl)-Amino]-2-Methyl-Propyl}- Phosphonic Acid 9 DB03003 Glutathione Sulfonic acid 261.371 38% 10 DB01910 Adenosyl-Ornithine 260.798 29.69% 11 DB01813 Pyridoxyl-Glutamic Acid-5-Monophosphate 260.557 40.9% 12 DB02011 N-(phosphonoacetyl)-L-Ornithine 260.026 41.85% 13 DB03327 {1-[(3-Hydroxy-Methyl-5-Phosphonooxy- 259.637 13.25% Methyl-Pyridin-4-Ylmethyl)-Amino]-Ethyl}- Phosphonic acid 14 DB02075 (1s)-1-(9-Deazahypoxanthin-9-yl)-1,4-Di 258.501 28.5% Deoxy-1,4-Imino-D-Ribitol-5-Phosphate 15 DB02077 L-N(Omega)-Nitroarginine-(4r)-Amino-L- 258.008 71.8% Proline Amide 16 DB01815 Nz-(Dicarboxymethyl)Lysine 257.918 22.68% 17 DB01974 2-Amino-3-[5-(Amino-Carboxy-Methyl)-2,3- 253.882 66.711% Dihydro-Isoxazol-3-Ylsulfanyl]-Propionic Acid 18 DB04323 2-Amino-3-(Cystein-S-Yl)-Isoxazolidin-5-Yl- 252.875 56.68% Acetic acid 19 DB03927 Glycyl-L-Alpha-Amino-Epsilon-Pimelyl-D- 252.376 29.859% Alanine 20 DB03582 N-2-Succinylornithine 252.353 19.97% 21 DB02537 2 -Hydroxy-5-({1-[(4-Methylphenoxy)Methyl]- 248.151 71.1% 3-Oxoprop-1-Enyl}Amino)-L-Tyrosin 22 DB01634 2-Oxy-4-Hydroxy-5-(2- 246.192 23.7% Hydrazinopyridine)Phenylalanine 23 DB04153 S-Hydroxymethyl Glutathione 245.035 58% 24 DB04649 TETRAHEDRAL INTERMEDIATE OF 244.418 20.09% BLASTICIDIN S 25 DB04778 SC45647 243.957 11.29% 26 DB02824 N-Pyridoxyl-Glycine-5-Monophosphate 243.609 77.97% 27 DB04701 S-METHYL-GLUTATHIONE 243.574 40.1% 28 DB01657 2-Amino-3-[4-Hydroxy-6-Oxo-3-(2-Phenyl- 243.414 22.9% Cyclopropylimino)-Cyclohexa-1,4-Dienyl]- Propionic acid 29 DB02941 3-(1-Aminoethyl)Nonanedioic Acid 243.33 69.8% 30 DB04684 BIS(HEXAMETHYLENE)TRIAMINE 242.609 9.3% 31 DB02492 Ghavamiol 242.096 17.4% 32 DB03427 Delta-(L-Alpha-Aminoadipoyl)-L-Cysteinyl-D- 241.85 13.3% Vinylglycine 33 D1303686 S-(P-Nitrobenzyl)Glutathione 240.981 63.83% 34 DB04762 N-PYRIDOXYL-D-GLUTAMIC ACID-5- 240.901 27.7% MONOPHOSPHATE 35 DB03602 S-Benzyl-Glutathione 240.844 36.5% 36 DB03566 Spermidine 239.222 68.98% 37 D1304808 Neamine 239.011 37.11% 38 DB04341 S-(3-Iodobenzyl)Glutathione 235.101 9.9% 39 DB01895 Aspartyl-Adenosine-5-Monophosphate 233.296 22.918% 40 DB03624 7-(Carboxyamino)-8-Amino-Nonanoic Acid 232.98 51.9% 41 DB04434 Naphthyridine Inhibitor 232.928 22.98% 42 DB04602 PUROMYCIN AMINONUCLEOSIDE-5- 249.924 12.9% MONOPHOSPHATE

[0022] Computer screening results show that all the compounds listed in the above table can effectively interact with PAICS, influence SAICAR synthesis, and thus reduce the accumulation of the toxic metabolite. Therefore, it is expected that these compounds can be developed as drug or health-care products for treating ADSL deficiency.

[0023] The pharmaceutically acceptable derivatives of the above compounds have the same parent core structures as the compounds per se, and can produce molecules having the same or similar activity as the original compounds through reactions such as hydrolysis and the like in vivo, resulting in the same or similar therapeutic efficacy.

[0024] The pharmaceutically acceptable derivatives of the compounds may particularly refer to simple derivatives thereof, and especially refer to one of lower ester, lower ether, lower alkyl substituent, pharmaceutical salt and lower amide thereof, i.e., derivatives obtained by condensation of carboxylic acid, alcohol, amine having 1 to 6, preferably 2 to 6, or 2 to 4 carbon atom(s) with the parent compounds.

[0025] The pharmaceutically acceptable pharmaceutical salts of the compounds can be synthesized from the parent compound by conventional chemical methods, such as the method described in Pharmaceutical Salts: Properties, Selection and Use, P Heinrich Stahl (Editor), Camille G Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. In general, such salts can be prepared by reacting free alkali of the compounds with an acid in water, organic solvent or a mixed solution of both; generally, a non-aqueous media can be used, such as ethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.

[0026] Acid addition salts can be prepared with various acids (inorganic acids and organic acids). The examples of the acid addition salts may include salts prepared from an acid which may be selected from a group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (such as L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetylamino benzoic acid, butyric acid, (+)-camphoric acid, camphor sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (such as D-glucuronic acid), glutamic acid (such as L-glutamic acid), -ketoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethylsulfonic acid, (+)-L-lactic acid, ()-DL-lactic acid, lactobionic acid, maleic acid, malic acid, ()-L-malic acid, malonic acid, ()-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxyl-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, sulfocyanic acid, p-toluenesulfonic acid, undecylenic acid and pentanoic acid, as well as acyl-amino acid and cation exchange resin.

[0027] Combined utilization of the drugs can improve therapeutic effect, and reduce toxic and side effects to a certain extent. Preferably, 2, 3, 4, 5 or more compounds or derivatives thereof can be simultaneously used as the active ingredients for treating ADSL deficiency.