On scaffold hopping: Challenges in the discovery of sulfated small molecules as mimetics of glycosaminoglycans

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:23

Article

Sidhu, Preetpal S.^1,2  Mosier, Philip D.^1,2  Zhou, Qibing³  Desai, Umesh R.^1,2 

[1] Virginia Commonwealth Univ, Dept Med Chem, Richmond, VA 23219 USA

[2] Virginia Commonwealth Univ, Inst Struct Biol & Drug Discovery, Richmond, VA 23219 USA

[3] Huazhong Univ Sci & Technol, Inst Mat Med, Coll Life Sci & Technol, Wuhan 430074, Hunan, Peoples R China

关键词: Allosteric inhibition;    Anticoagulants;    Scaffold hopping;    Thrombin;    Virtual screening;   

DOI  :  10.1016/j.bmcl.2012.10.079

来源: Elsevier

【 摘 要 】

The design of sulfated, small, nonsaccharide molecules as modulators of proteins is still in its infancy as standard drug discovery tools such as library of diverse sulfated molecules and in silico docking and scoring protocol have not been firmly established. Databases, such as ZINC, contain too few sulfate-containing nonsaccharide molecules, which severely limits the identification of new hits. Lack of a generally applicable protocol for scaffold hopping limits the development of sulfated small molecules as synthetic mimetics of the highly sulfated glycosaminoglycans. We explored a sequential ligand-based (LBVS) and structure-based virtual screening (SBVS) approach starting from our initial discovery of monosulfated benzofurans to discover alternative scaffolds as allosteric modulators of thrombin, a key coagulation enzyme. Screening the ZINC database containing nearly 1 million nonsulfated small molecules using a pharmacophore developed from the parent sulfated benzofurans followed by a genetic algorithm-based dual-filter docking and scoring screening identified a group of 10 promising hits, of which three top-scoring hits were synthesized. Each was found to selectively inhibit human alpha-thrombin suggesting the possibility of this approach for scaffold hopping. Michaelis-Menten kinetics showed allosteric inhibition mechanism for the best molecule and human plasma studies confirmed good anticoagulation potential as expected. Our simple sequential LBVS and SBVS approach is likely to be useful as a general strategy for identification of sulfated small molecules hits as modulators of glycosaminoglycan-protein interactions. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

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