臺灣博碩士論文加值系統

本研究合成各系列之苯胺雙雜環類衍生物13-30、35-45和47-61，並對其抗C型肝炎病毒進行活性評估和生物活性之探討。結果發現所合成的衍生物對C型肝炎病毒皆呈現出抑制活性的反應，我們並藉此進一步釐清其結構與活性上的關係。在苯胺喹啉類衍生物中，其苯環的第三位以強拉電子基取代的化合物25 (EC50 = 7 ?嵱) 對C型肝炎病毒NS3/4A蛋白酶顯示出抑制活性。在苯胺香豆素類衍生物中，其苯環上以三個甲氧基取代的化合物39 (EC50 = 12 ?嵱) 是第一個被發現藉由誘導干擾素-調節抗病毒反應而有效抑制C型肝炎病毒複製的香豆素類衍生物。而在最後一類衍生物中，發現化合物59 (EC50 = 8 ?嵱) 表現出非競爭性抑制NS5B聚合酶而具有抑制C型肝炎病毒複製的活性，並由電腦分子模擬計算出與C型肝炎病毒NS5B聚合酶的最佳結合構型位於Thumb II Pocket。此外，化合物39及59與干擾素、telaprevir、BMS790052和PSI7977合併使用後對抑制C型肝炎病毒的複製呈現協同作用。由這些結果推測，此三類衍生物具備發展成為新型抗C型肝炎病毒小分子抑制劑的潛力。

In this study, the anti-HCV activities of the synthesized series of anilinoheterobicyclic derivatives 13-30, 35-45, and 47-61 were evaluated and their biological activities were discussed. A significant result was found that these synthesized derivatives were active against HCV. Based on this outcome, the relationships of their structures and activities were further illustrated. Among anilinoquinolines, compound 25 (EC50 = 7 ?嵱) with a strong EWG substituent on C3 of phenyl ring showed anti-HCV activity against NS3/4A protease. Among anilinocoumarins, compound 39 (EC50 = 12 ?嵱) with trimethoxy substituents on the phenyl ring was the first report which demonstrated coumarin-like derivatives inhibiting viral replication through an induction of IFN-mediated anti-viral response. Among the last part of derivatives, compound 59 (EC50 = 8 ?嵱) was observed to against NS5B polymerase by a non-competitive mode of inhibition. The best binding pose which calculated by computer molecular modeling of compound 59 was located in the Thumb II Pocket of HCV RdRp. Moreover, compounds 39 and 59 displayed the synergism decreasing HCV RNA levels by combination with IFN, telaprevir, BMS790052 or PSI7977. As a consequence, it is suggested that these three series of synthesized derivatives be promising to develop as novel anti-HCV small molecule inhibitors.

誌謝 I
中文摘要 II
Abstract III
目次 IV
表目錄 VII
圖目錄 VIII
綱目目錄 X
第一章 緒論 1
第一節 前言 1
第二節 研究動機與目的 8
第二章 化學合成方法 16
第一節 苯胺喹啉類衍生物的合成 16
第二節 苯胺香豆素類衍生物的合成 17
第三節 苯胺苯并噻唑類衍生物的合成 19
第三章 藥理活性的結果與討論 20
第一節 苯胺喹啉類衍生物的生物活性實驗結果與討論 20
第二節 苯胺香豆素類衍生物的生物活性實驗結果與討論 27
第三節 苯胺苯并噻唑類衍生物的生物活性實驗結果與討論 39
第四章 結論 56
第五章 化學合成實驗部分 60
第一節 溶劑及處理過程 60
第二節 儀器與試藥 60
第六章 藥理活性實驗部分 112
第一節 研究材料 112
第二節 各項活性試驗方法 114
第七章 參考文獻 121
第八章 研究成果目錄 131
(一) 投稿論文 131
(二) 學會口頭發表論文 132
(三) 學會壁報發表論文 132
第九章 期刊論文抽印本 134

1.Choo, Q. L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley, D. W.; Houghton, M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989, 244, 359.
2.NIH Consensus Statement on Management of Hepatitis C: 2002. NIH state-of-the-science statement on endoscopic retrograde cholangiopancreatography (ERCP) for diagnosis and therapy. NIH Consens State Sci Statements 2002, 19, 1.
3.Koziel, M. J.; Peters, M. G. Viral hepatitis in HIV infection. N. Engl. J. Med. 2007, 356, 1445.
4.Chen, S. L.; Morgan, T. R. The natural history of hepatitis C virus (HCV) infection. Int. J. Med. Sci. 2006, 3, 47.
5.Zoulim, F.; Chevallier, M.; Maynard, M.; Trepo, C. Clinical consequences of hepatitis C virus infection. Rev. Med. Virol. 2003, 13, 57.
6.Hsieh, P. C.; Kuo, H. T.; Cho, W. C.; Liao, Y. L.; Lin, C. N. The genotype of hepatitis C virus has important clinical and therapeutic implications. J. Intern. Med. Taiwan 2009, 20, 309.
7.Brass, V.; Moradpour, D.; Blum, H. E. Molecular virology of hepatitis C virus (HCV): 2006 update. Int. J. Med. Sci. 2006, 3, 29.
8.Lindenbach, B. D.; Rice, C. M. Unravelling hepatitis C virus replication from genome to function. Nature 2005, 436, 933.
9.Gordon, C. P.; Keller, P. A. Control of hepatitis C: a medicinal chemistry perspective. J. Med. Chem. 2005, 48, 1.
10.Simmonds, P. Genetic diversity and evolution of hepatitis C virus – 15 years on. J. Gen. Virol. 2004, 85, 3173.
11.Zein, N. N. Clinical significance of hepatitis C virus genotypes. Clin. Microbiol. Rev. 2000, 13, 223.
12.Han, J. H.; Shyamala, V.; Richman, K. H.; Brauer, M. J.; Irvine, B.; Urdea, M. S.; Tekamp-Olson, P.; Kuo, G.; Choo, Q. L.; Houghton, M. Characterization of the terminal regions of hepatitis C viral RNA: identification of conserved sequences in the 5’ untranslated region and poly(A) tails at the 3’ end. Proc. Natl. Acad. Sci. U S A 1991, 88, 1711.
13.Otto, G. A.; Puglisi, J. D. The pathway of HCV IRES-mediated translation initiation. Cell 2004, 119, 369.
14.Spahn, C. M. T.; Kieft, J. S.; Grassucci, R. A.; Penczek, P. A.; Zhou, K.; Doudna, J. A.; Frank, J. Hepatitis C virus IRES RNA-induced changes in the conformation of the 40 S ribosomal subunit. Science 2001, 291, 1959.
15.Hope, R. G.; Murphy, D. J.; McLauchlan, J. The domains required to direct core proteins of hepatitis C virus and GB virus-B to lipid droplets share common features with plant oleosin proteins. J. Biol. Chem. 2002, 277, 4261.
16.Lerat, H.; Honda, M.; Beard, M. R.; Loesch, K.; Sun, J.; Yang, Y.; Okuda, M.; Gosert, R.; Xiao, S. Y.; Weinman, S. A.; Lemon, S. M. Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 2002, 122, 352.
17.Moriya, K.; Fujie, H.; Shintani, Y.; Yotsuyanagi, H.; Tsutsumi, T.; Ishibashi, K.; Matsuura, Y.; Kimura, S.; Miyamura, T.; Koike, K. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat. Med. 1998, 4, 1065.
18.Hofmann, W. P. and Zeuzem, S. A new standard of care and race towards IFN-free therapy. Nat. Rev. Gastroenterol. Hepatol. 2012, 9, 67.
19.Pestova, T. V.; Shatsky, I. N.; Fletcher, S. P.; Jackson, R, J.; Hellen, C. U. A prokaryotic-like mode of cytoplasmic eukaryotic ribosome binding to the initiation codon during internal translation initation of hepatitis C and classical swine fever virus? RNAs. Genes. Dev. 1998, 12, 67.
20.Ramesh, E.; Manian, R. D. R. S.; Raghunathan, R.; Sainath, S.; Raghunathan, M. Synthesis and antibacterial property of quinolines with potent DNA gyrase activity. Bioorg. Med. Chem. 2009, 17, 660.
21.Musiol, R.; Jampilek, J.; Kralova, K.; Richardson, D. R.; Kalinowski, D.; Podeszwa, B.; Finster, J.; Niedbala, H.; Palka, A.; Polanski, J. Investigating biological activity spectrum for novel quinoline analogues. Bioorg. Med. Chem. 2007, 15, 1280.
22.Musiol, R.; Jampilek, J.; Buchta, V.; Silva, L.; Niedbala, H.; Podeszwa, B.; Palka, A.; Majerz-Maniecka, K.; Oleksyn, B.; Polanski, J. Antifungal properties of new series of quinoline derivatives. Bioorg. Med. Chem. 2006, 14, 3592.
23.Priya, N.; Gupta, A.; Chand, K.; Singh, P.; Kathuria, A.; Raj, H. G.; Parmar, V. S.; Sharma, S. K. Characterization of 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl acetate as an effective antiplatelet agent. Bioorg. Med. Chem. 2010, 18, 4085.
24.Kuo, S. C.; Lee, H. Z.; Juang, J. P.; Lin, Y. T.; Wu, T. S.; Chang, J. J.; Lednicer, D.; Paull, K. D.; Lin, C. M. Synthesis and cytotoxicity of 1,6,7,8-substituted 2- (4’-substituted phenyl)-4-quinolones and related compounds: identification as antimitotic agents interacting with tubulin. J. Med. Chem. 1993, 36, 1146.
25.Vazquez, M. T.; Romero, M.; Pujol, M. D. Synthesis of novel 2,3-dihydro-1,4-dioxino[2,3-g]quinoline derivatives as potential antitumor agents. Bioorg. Med. Chem. 2004, 12, 949.
26.Chang, F. S.; Chen, W.; Wang, C.; Tzeng, C. C.; Chen, Y. L. Synthesis and antiproliferative evaluations of certain 2-phenylvinylquinoline (2-styrylquinoline) and 2-furanylvinylquinoline derivatives. Bioorg. Med. Chem. 2010, 18, 124.
27.Ahmed, N.; Brahmbhatt, K. G.; Sabde, S.; Mitra, D.; Singh, I. P.; Bhutani, K. K. Investigating biological activity spectrum for novel quinoline analogues. Bioorg. Med. Chem. 2010, 18, 2872.
28.Melagraki, G.; Afantitis, A.; Sarimveis, H.; Koutentis, P. A.; Markopoulos, J.; Igglessi-Markopoulou, O. Identification of a series of novel derivatives as potent HCV inhibitors by a ligand-based virtual screening optimized procedure. Bioorg. Med. Chem. 2007, 15, 7237.
29.Vogel, A. Darstellung von Benzoesaure aus der Tonka-Bohne und aus den Meliloten-oder Steinklee-Blumen. Annalen der Physik 1820, 64, 161.
30.Murray, R. D. H. In Progress in the Chemistry of Natural Products; Herz, W.; Grisebach, H.; Kirby, G. W., Eds.; Springer-Verlag: New York, 1978, 199.
31.Jeanneret, V.; Vogel, P.; Renaut, P.; Millet, J.; Theveniaux, J.; Barberousse, V. Carbaxylosides of 4-ethyl-2-oxo-2H-benzopyran-7-yl as nonhydrolyzable, orally active venous antithrombotic agents. Bioorg. Med. Chem. Lett. 1998, 8, 1687.
32.Musiciki, B.; Periers, A. M.; Laurin, P.; Ferroud, D.; Benedetti,Y.; Lachaud, S.; Chatreaux, F.; Haesslein, J. L.; Iltis, A.; Pierre, C.; Khider, J.; Tessot, N.; Airault, M.; Demassey, J.; Dupuis-Hamelin, C.; Lassaigne, P.; Bonnefoy, A.; Vicat, P.; Klich, M. Improved antibacterial activities of coumarin antibiotics bearing 5’,5’-dialkylnoviose: biological activity of RU79115. Bioorg. Med. Chem. Lett. 2000, 10, 1695.
33.Takeuchi, Y.; Xie, L.; Cosentino, L. M.; Lee, K. H. Anti-AIDS agents-XXVIII. Synthesis and anti-HIV activity of methoxy substituted 3'',4''-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) analogues. Bioorg. Med. Chem. Lett. 1997, 7, 2573.
34.Neyts, J.; Clercq, E. D.; Singha, R.; Chang, Y. H.; Das, A. R.; Chakraborty, S. K.; Hong, S. C.; Tsay, S. C.; Hsu, M. H.; Hwu, J. R. Structure-activity relationship of new anti-hepatitis C virus agents: heterobicycle-coumarin conjugates. J. Med. Chem. 2009, 52, 1486.
35.Hwu, J. R.; Lin, S. Y.; Tsay S. C.; Clercq, E. D.; Leyssen, P.; Neyts, J. Coumarin-purine ribofuranoside conjugates as new agents against hepatitis C virus. J. Med. Chem. 2011, 54, 2114.
36.Beaulieu, P. L.; Bousquet, Y.; Gauthier, J.; Gillard, J.; Marquis, M.; McKercher, G.; Pellerin, C.; Valois, S.; Kukolj, G. Non-nucleoside benzimidazole-based allosteric inhibitors of the hepatitis C virus NS5B polymerase: inhibition of subgenomic hepatitis C virus RNA replicons in Huh7 cells. J. Med. Chem. 2004, 47, 6884.
37.Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.; Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: structure-activity relationship studies and identification of a potent and highly selective inhibitor JTK-109. J. Med. Chem. 2006, 49, 4721.
38.Vliegen, I.; Paeshuyse, J.; Burghgraeve, T. D.; Lehman, L. S.; Paulson, M.; Shih, I. H.; Mabery, E.; Boddeker, N.; Clercq, E. D.; Reiser, H.; Oare, D.; Lee, W. A.; Zhong, W.; Bondy, S.; Purstinger, G.; Neyts, J. Substituted imidazopyridines as potent inhibitors of HCV replication. J. Hepatol. 2009, 50, 999.
39.Ivashkina, N.; Wolk, B.; Lohmann, V.; Bartenschlager, R.; Blum, H. E.; Penin, F.; Moradpour, D. The hepatitis C virus RNA-dependent RNA polymerase membrane insertion sequence is a transmembrane segment. J. Virol. 2002, 76, 13088.
40.Moradpour, D.; Brass, V.; Bieck, E.; Friebe, P.; Gosert, R.; Blum, H. E.; Bartenschlager, R.; Penin, F.; Lohman, V. Membrane association of the RNA-dependent RNA polymerase is essential for hepatitis C virus RNA replication. J. Virol. 2004, 78, 13278.
41.Schmidt-Mende, J.; Bieck, E.; Hugle, T.; Penin, F.; Rice, C. M.; Blum, H. E.; Moradpour, D. Determinants for membrane association of the hepatitis C virus RNA-dependent RNA polymerase. J. Biol. Chem. 2001, 276, 44052.
42.You, S.; Stump, D. D.; Branch, A. D.; Rice, C. M. A cis-acting replication element in the sequence encoding the NS5B RNA-dependent RNA polymerase is required for hepatitis C virus RNA replication. J. Virol. 2004, 78, 1352.
43.LigandFit, D. S. Accelrys Software Inc.: 10188 Telesis Court, Suite 100 San Diego, CA 92121, USA.
44.Lee, J. C.; Tseng, C. K.; Chen, K. J.; Huang, K. J.; Lin, C. K.; Lin, Y. T. A cell-based reporter assay for inhibitor screening of hepatitis C virus RNA-dependent RNA polymerase. Anal. Biochem. 2010, 403, 52.
45.Lin, Y. T.; Huang, K. J.; Tseng, C. K.; Chen, K. J.; Wang, H. M.; Lee, J. C. Efficient in silico assay of inhibitors of hepatitis C virus RNA-dependent RNA polymerase by structure-based virtual screening and in vitro evaluation. Assay Drug Dev. Technol. 2011, 9, 290.
46.John, E. V. O.; Israelstam, S. S. Use of cation exchange resins in organic reactions. I. The von Pechmann reaction. J. Org. Chem. 1961, 26, 240.
47.Panetta, J. A.; Rapoport, H. New syntheses of coumarins. J. Org. Chem. 1982, 47, 946.
48.Mali, R. S.; Yadav, V. J. Convenient synthesis of naturally occurring coumarins, (2-oxo-2H-benzopyrans) and 4-methylcoumarins (4-methyl-2-oxo-2H-benzopyrans). Synthesis 1977, 464.
49.Hepworth, J. D. In Comprehensive Heterocyclic Chemistry, Vol. 3; Boulton, A. J.; McKillop, A., Eds.; Pergamon: Oxford, 1984, 881.
50.Bogdal, D. Coumarins: fast synthesis by Knoevenagel condensation under microwave irradiation. J. Chem. Res. Synop. 1998, 468.
51.Fall, Y.; Teran, C.; Teijeira, M.; Santana, L.; Uriarte, E. Synthesis of new 4-cyclohexylcoumarin derivatives. Synthesis 2000, 643.
52.Fall, Y.; Santana, L.; Teijeira, M.; Uriarte, E. A convenient synthesis of benzofuran-3-acetic acids. Heterocycles 1995, 41, 647.
53.Kaye, P. T.; Musa, M. A. A convenient and improved Baylis–Hillman synthesis of 3-substututed 2H-1-benzopyran-2-ones. Synthesis 2002, 18, 2701.
54.Kaye, P. T.; Musa, M. A.; Nocanda X. W. Efficient and chemoselective access to 3-(chloromethyl)coumarins via direct cyclisation of unprotected Baylis–Hillman adducts. Synthesis 2003, 4, 531.
55.Lee, J. C.; Shih, Y. F.; Hsu, S. P.; Chang, T. Y.; Chen, L. H.; Hsu, J. T. A. Development of a cell-based assay for monitoring specific hepatitis C virus NS3/4A protease activity in mammalian cells. Anal. Biochem. 2003, 316, 162.
56.Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.; Bolger, G.; Bonneau, P.; Bos, M.; Cameron, D. R.; Cartier, M.; Cordingley, M. G.; Faucher, A. M.; Goudreau, N.; Kawai, S. H.; Kukolj, G.; Lagace, L.; LaPlante, S. R.; Narjes, H.; Poupart, M. A.; Rancourt, J.; Sentjens, R. E.; St George, R.; Simoneau, B.; Steinmann, G.; Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong, C. L.; Llinas-Brunet, M. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003, 426, 186.
57.Cheney, I. W.; Lai, V. C. H.; Zhong, W.; Beodhag, T.; Dempsey, S.; Lim, C.; Hong, Z.; Lau, J. Y. N.; Tam, R. C. Comparative analysis of anti-hepatitis C virus activity and gene expression mediated by alpha, beta, and gamma interferons. J. Virol. 2002, 76, 11148.
58.Lam, A. M.; Espiritu, C.; Bansal, S.; Micolochick Steuer, H. M.; Niu, C.; Zennou, V.; Keilman, M.; Zhu, Y.; Lan, S.; Otto, M. J.; Furman, P. A. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob. Agents Chemother. 2012, 56, 3359.
59.Lemm, J. A.; Leet, J. E.; O’Boyle II, D. R.; Romine, J. L.; Huang, X. S.; Schroeder, D. R.; Alberts, J.; Cantone, J. L.; Sun, J. H.; Nower, P. T.; Martin, S. W.; Serrano-Wu, M. H.; Meanwell, N. A.; Snyder, L. B.; Gao, M. Discovery of potent hepatitis C virus NS5A inhibitors with dimeric structures. Antimicrob. Agents Chemother. 2011, 55, 3795.
60.Chou, T. C.; Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 1984, 22, 27.
61.Okamoto, T.; Kobayashi, T.; Yoshida, S. Chemical aspects of coumarin compounds for the prevention of hepatocellular carcinomas. Curr. Med. Chem.: Anti-Cancer Agents. 2005, 5, 47.
62.Lineweaver, H.; Burk, D. The determination of enzyme dissociation constants. J. Am. Chem. Soc. 1934, 56, 658.
63.Antonysamy, S. S.; Aubol, B.; Blaney, J.; Browner, M. F.; Giannetti, A. M.; Harris, S. F.; Hebert, N.; Hendle, J.; Hopkins, S.; Jefferson, E.; Kissinger, C.; Leveque, V.; Marciano, D.; McGee, E.; Najera, I.; Nolan, B.; Tomimoto, M.; Torres, E.; Wright, T. Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 2990.
64.Le Pogam, S.; Kang, H.; Harris, S. F.; Leveque, V.; Giannetti, A. M.; Ali, S.; Jiang, W. R.; Rajyaguru, S.; Tavares, G.; Oshiro, C.; Hendricks, T.; Klumpp, K.; Symons, J.; Browner, M. F.; Cammack, N.; Najera, I. Selection and characterization of replicon variants dually resistant to thumb- and palm-binding nonnucleoside polymerase inhibitors of the hepatitis C virus. J. Virol.2006, 80, 6146.
65.Molina, P.; Alajarin, M.; Vidal, A.; Sanchez-Andrada, P. C=C-Conjugated carbodiimides as 2-azadienes in intramolecular [4+2] cycloadditions. One-pot preparation of quinoline, ??-carboline, and quinindoline derivatives. J. Org. Chem. 1992, 57, 929.
66.Venkatesh, C.; Sundaram, G. S. M.; Ila, H.; Junjappa, H. Palladium-catalyzed intramolecular N-arylation of heteroarenes: A novel and efficient route to benzimidazo[1,2-a]quinolines. J. Org. Chem. 2006, 71, 1280.
67.Bennett, G. M.; Crofts, P. C.; Hey, D. H. Synthetic antimalarials. XXXV. Further arylaminodialkylaminoalkylaminoquinoline derivatives. J. Chem. Soc. 1949, 227.
68.Bradley, W.; Wright, I. Metal derivatives of N,N’-diarylamidines. J. Chem. Soc. 1956, 640.
69.Shen, G.; Lv, X.; Bao, W. Synthesis of N-substituted-2-aminobenzothiazoles by ligand-free copper(I)-catalyzed cross-coupling reaction of 2-haloanilines with isothiocyanates. Eur. J. Org. Chem. 2009, 34, 5897.
70.Ding, Q.; Cao, B.; Liu, X.; Zong, Z.; Peng, Y. Y. Synthesis of 2-aminobenzothiazole via FeCl3-catalyzed tandem reaction of 2-iodoaniline with isothiocyanate in water. Green Chem. 2010, 12, 1607.
71.Yang, J.; Li, P.; Wang, L. Merrifield resin supported phenanthroline-Cu(I): a highly efficient and recyclable catalyst for the synthesis of 2-aminobenzothiazoles via the reaction of 2-haloanilines with isothiocyanates. Tetrahedron 2011, 67, 5543.
72.Bartenschlager R. Hepatitis C virus replicones: potential role for drug development. Nat. Rev. Drug Discov. 2002, 11, 911.
73.Lee, J. C.; Chen, W. C.; Wu, S. F.; Tseng, C. K.; Chiou, C. Y.; Chang, F. R.; Hsu, S. H.; Wu, Y. C.; Anti-hepatitis C virus activity of Acacia confusa extract via suppressing cyclooxygenase-2. Antivir. Res. 2011, 89, 35.
74.Engel, P. C.; Dalziel, K. Kinetic studies of glutamate dehydrogenase with glutamate and norvaline as substrates. Coenzyme activation and negative homotropic interactions in allosteric enzymes. Biochem. J. 1969, 115, 621.
75.Brandt, R. B.; Laux, J. E.; Yates, S. W. Calculation of inhibitor Ki and inhibitor type from the concentration of inhibitor for 50% inhibition for Michaelis-Menten enzymes. Biochem. Med. Metab. Biol. 1987, 37, 344.
76.Kerwin, S. M. ChemBioOffice Ultra 2010 suite. J. Am. Chem. Soc. 2010, 132, 2466.
77.Vanommeslaeghe, K.; Hatcher, E.; Acharya, C.; Kundu, S.; Zhong, S.; Shim, J.; Darian, E.; Guvench, O.; Lopes, P.; Vorobyov, I.; Mackerell, A. D. Jr. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem. 2010, 31, 671.
78.Vanommeslaeghe, K.; MacKerell, A. D. Jr. Automation of the CHARMM General Force Field (CGenFF) I: bond perception and atom typing. J. Chem. Inf. Model. 2012, 52, 3144.
79.Vanommeslaeghe, K.; Raman, E. P.; MacKerell, A. D. Jr. Automation of the CHARMM General Force Field (CGenFF) II: assignment of bonded parameters and partial atomic charges. J. Chem. Inf. Model. 2012, 52, 3155.
80.Muegge, I.; Martin, Y. C. A general and fast scoring function for protein-ligand interactions: a simplified potential approach. J. Med. Chem. 1999, 42, 791.
81.Muegge, I. PMF scoring revisited. J. Med. Chem. 2006, 49, 5895.