- Approaches to design non-covalent inhibitors for human granzyme B (hGrB)
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A structure-based design campaign for non-covalent small molecule inhibitors of human granzyme B was carried out by means of a virtual screening strategy employing three constraints and probe site-mapping with FTMAP to identify ligand "hot spots". In addition, new scaffolds of diverse structures were subsequently explored with ROCS shape-based superposition methods, following by Glide SP docking, induced fit docking and analysis of QikProp molecular properties. Novel classes of moderately active small molecule blockers (≥25 μM IC50 values) from commercially available libraries were identified, and three novel scaffolds have been synthesized by multi-step procedures. Furthermore, we provide an example of a comprehensive structure-based drug discovery approach to non-covalent inhibitors that relies on the X-ray structure of a covalently bound ligand and suggest that the design path may be compromised by alternative and unknown binding poses. This journal is
- Kim, Mi-Sun,Buisson, Lauriane A.,Heathcote, Dean A.,Hu, Haipeng,Braddock, D. Christopher,Barrett, Anthony G. M.,Ashton-Rickardt, Philip G.,Snyder, James P.
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p. 8952 - 8965
(2015/02/19)
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- A facile one-pot synthesis of 1-substituted tetrazole-5-thiones and 1-substituted 5-alkyl(aryl)sulfanyltetrazoles from organic isothiocyanates
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Treatments of organic isothiocyanates (R-NCS) with NaN3 in the presence of pyridine in water at room temperature gave corresponding various organic tetrazole-thiones, [S=CN4(R)] (R = alkyl or aryl). Isolated products are obtained as white or yellow solids in good yields (76-97%). The molecular structure by X-ray diffraction study for one of products shows the proposed formation. In addition, one-pot synthesis of 1- substituted 5-alkyl(or aryl)sulfanyltetrazoles has been demonstrated. Addition of alkyl or aryl halides into the mixture of organic isothiocyanates, NaN3, and pyridine in water at room temperature exclusively formed 1- substituted 5-alkyl(or aryl)sulfanyltetrazoles (S-derivatives) in high yields.
- Han, Sam Yong,Lee, Je Woo,Kim, Hee-Jung,Kim, Yong-Joo,Lee, Soon W.,Gyoung, Young Soo
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experimental part
p. 55 - 59
(2012/03/09)
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- Synthesis of unsymmetrical sulfides derived from tetrazole-5-thiols
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A series of unsymmetrical sulfides derived from I-substituted tetrazole-5-thiols was prepared by fusion of the corresponding 1-R-tetrazole-5-thiol sodium salt with 1-R′-5-halotetrazole. The structure was confirmed by 1H NMR and 13C NMR spectra. The target compounds were prepared in 50-80% yields.
- Hrabalek,Pus,Baranek,Kunes,Palat
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p. 183 - 189
(2007/10/03)
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- Product and preparation of 1H-tetrazole-5-thiol derivatives
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The process for preparation of and the intermediate compounds such as 1H-tetrazole-5-thiol having the formula STR1 wherein R1 is alkyl, aminoalkyl, acylaminoalkyl, aryl, alkoxycarbonylaminoalkyl, halogen-substituted aryl or alkylamino-substituted aryl and R2 is hydrogen or arakyl, preferably benzyl. The compound is produced by reacting a substituted thiosemicarbazide with an aralkyl chloride, subjecting the resultant compound to diazotization, and reacting the resultant compound with a Friedel Crafts catalyst. Optionally, this may be further hydrolyzed when R1 is aminoalkyl and/or converted to conventional salts.
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