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Constructing an Integrated Compound Library for Efficient Structure-based Virtual Screening
Lee, Hui Sun,Choi, Jiwon,Qinqin Ma,Ko, Yoonae,Yoon, Sukjoon Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.2
Structure-based virtual screening is now essential technique in early stage drug discovery. A critical infrastructure needed for structure-based virtual screening is a suitable, large scale and easy to access database of purchasable compounds. We have therefore built an integrated compound library for efficient structure-based virtual screening. Here, we present an overview of the library preparation Compounds collected from a variety of vendors as 2D SDfiles were converted into 3D structures containing all the hydrogen atoms. We merged all the 3D converted compounds into a single file and then filtered it to optimize the library for drug discovery usage. Moreover, we generated a conformer library of possible conformer structures for each compound in order to utilize it in ligand-centric virtual screening by shape matching. Our constructing integrated compound library can be applied to various steps of structure-based virtual screening and will contribute to enhancing the efficiency of the virtual screening for drug discovery.
Kim, Hee-Young,Kong, Sunju,Oh, Sangmi,Yang, Jaewon,Jo, Eunji,Ko, Yoonae,Kim, Soo-Hyun,Hwang, Jong Yeon,Song, Rita,Windisch, Marc P. Elsevier 2016 ANTIVIRAL RESEARCH Vol.129 No.-
<P>Upon screening synthetic small molecule libraries with the infectious hepatitis C virus (HCV) cell culture system, we identified a benzothiazepinecarboxamide (BTC) scaffold that inhibits HCV. A structure-activity relationship (SAR) study with BTC5 was performed, and modifications that led to nanomolar antiviral activity and improved the selective index (CC50/EC50) by more than 1000-fold were identified. In addition, a pharmacophore modeling study determined that the tricyclic core and positive charge on the piperidine moiety were essential for antiviral activity. Furthermore, we demonstrated that BTC interferes with HCV glycoprotein E1/E2-mediated viral entry and the generation of infectious virions by using HCV pseudoparticle and cell culture supernatant transfer assays, respectively. BTC showed potent antiviral activity against HCV genotype 2 (EC50 = 0.01 +/- 0.01 mu M), but was less potent against a genotype 1/2 chimeric virus (EC50 = 2.71 +/- 0.05 mu M), which expressed the structural proteins of HCV genotype 1. In summary, we identified, optimized, and characterized novel BTC inhibitors that interfere with early and late steps of the HCV viral life cycle. (C) 2016 Elsevier B.V. All rights reserved.</P>
Kang, Sunhee,Kim, Ryang Yeo,Seo, Min Jung,Lee, Saeyeon,Kim, Young Mi,Seo, Mooyoung,Seo, Jeong Jea,Ko, Yoonae,Choi, Inhee,Jang, Jichan,Nam, Jiyoun,Park, Seijin,Kang, Hwankyu,Kim, Hyung Jun,Kim, Jungjun American Chemical Society 2014 Journal of medicinal chemistry Vol.57 No.12
<P>A critical unmet clinical need to combat the global tuberculosis epidemic is the development of potent agents capable of reducing the time of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis therapy. In this paper, we report on the optimization of imidazo[1,2-<I>a</I>]pyridine amide (IPA) lead compound <B>1</B>, which led to the design and synthesis of Q203 (<B>50</B>). We found that the amide linker with IPA core is very important for activity against <I>Mycobacterium tuberculosis</I> H37Rv. Linearity and lipophilicity of the amine part in the IPA series play a critical role in improving in vitro and in vivo efficacy and pharmacokinetic profile. The optimized IPAs <B>49</B> and <B>50</B> showed not only excellent oral bioavailability (80.2% and 90.7%, respectively) with high exposure of the area under curve (AUC) but also displayed significant colony-forming unit (CFU) reduction (1.52 and 3.13 log<SUB>10</SUB> reduction at 10 mg/kg dosing level, respectively) in mouse lung.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2014/jmcmar.2014.57.issue-12/jm5003606/production/images/medium/jm-2014-003606_0013.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm5003606'>ACS Electronic Supporting Info</A></P>