We will be making a regular point of providing you with the latest publications, reports and papers including developments and products from BioSolveIT and its associated owners.

Discovery of Novel Nitrobenzothiazole Inhibitors for Mycobacterium tuberculosis ATP Phosphoribosyl Transferase (HisG) through Virtual Screening
Yoonsang Cho, Thomas R. Ioerger, and James C. Sacchettini
J. Med. Chem. 51(19):5984-92. (2008)

FlexX Fragment Docking Works! In his blog, Dr. Teddy Zartler says:
"It is interesting to see docking actually working with fragments. It has always been my impression that you can get a lot of poses out of a dock with a fragment. With this paper I am proven wrong."
The JMC publication describes a FlexX and Gold virtual screen of ½ million compounds from the Chembridge and NCI libraries to discover micromolar inhibitors of HisG, an ATP-phosphoribosyl transferase (ATPPRTase). FlexX was used to validate the top 1% of hits obtained with an initial screen with Gold. Furthermore, a consensus scoring re-ranking protocol was used from SYBYL which combines scores from FlexX, PMF, Gold, Chemscore and Dock. 50 compounds were selected for testing, and 7 of these had inhibition activity with 5 compounds having IC50's at or below 10 µM. Based on the initial hits a search of the ChemBridge database for additional nitrobenzothiazole or structural analogues was performed yielding 4854 compounds. These were filtered with Lipinski's rules and then solely docked with FlexX and re-scored in SYBYL. From this screen three micromolar hits were identified, with one having an IC50 value of 5.5µM.
Link to article

In Silico Screening for PTPN22 Inhibitors: Active Hits from an Inactive Phosphatase Conformation
Shuangding Wu, Massimo Bottini, Robert C. Rickert, Tomas Mustelin, and Lutz Tautz
ChemMedChem. 2009 Jan 28. [Epub ahead of print]

A Successful, Protein Conformation Dependent Docking:
The authors describe a virtual screen of lymphoid phosphatase Lyp (PTPN22), a protein involved in type 1 diabetes and other autoimmune diseases. FlexX was used in conjunction with ICM to screen a library of 27030 'drug-like' molecules against two different 3D structures, one an inactive 'open' conformation and the other a active 'closed' conformation. High docking scores were only exhibited with the 'open' conformation. The 20 best-ranked compounds were chosen for experimental testing from each of the 4 virtual screens run and 71 compounds were purchased due to overlap in the hits obtained. A variety of 2-benzamidobenzoic acid (2-BBA) derivatives were identified with IC50 values ranging from 0.947 to 22.9 µM.
Link to article

Identification of Novel HCV RNA-dependent RNA polymerase Inhibitors Using Pharmacophore-Guided Virtual Screening
Jinyoung Kim, Ki-sun Kim, Dong-Eun Kim, and Youhoon Chong
J. Chem. Inf. Model. 48(5):1092-103. (2008)

Yet another FlexX-Pharm Docking Inhibitor Discovery:
The paper presents a pharmacophore guided virtual screening project of the 37, 447 compounds of the LeadQuest library against hepatitis C virus RNA dependent RNA polymerase. The initial screen using a UNITY base pharmacophore derived from previous computational and experimental information was used to identify 227 compounds. These were subsequently docked with FlexX-Pharm and re-ranked using CScore. Of the 227 compounds previously identified 103 were docked correctly, with the top scoring 40 molecules selected for biological testing. A cell-based assay at 10µM was used to estimate activity of the compounds, which showed a cell viability range of 1.26% - 124.87%. T29, the most potent compound, had shown the best docking pose which perfectly matched with the divalent metal ions, two hydrogen bond acceptor sites and the hydrophobic aryl-binding domain in the target enzyme.
Link to article