In the last issue we gave you an overview of features that will come with the major release 2.0. This time we will go into more detail with regard to two particularly interesting extensions included in the big next release.

Compatibility of the main new modules: It is by no means obvious how to combine the definition of a receptor-based pharmacophore in FlexX-Pharm with the variation of side chain conformations in FlexE. Therefore it took us considerable time and effort to achieve intercompatibility between most of the major FlexX* modules. Read the details!

SMARTS in FlexX, FlexS and FTrees: SMILES and SMARTS, the de facto standards for the formulation of chemical rules in line notation will be introduced to the world of Flex* and FTrees with the Release 2.0. This facility will give to you a highly enhanced capability when working with our tools: All problems related to substructure detection, structure initialization, manipulation and filtering will be much more powerful and easier to handle than before. Read the details!

May 2004 marked the achievement of a major milestone in our cooperation project with Aventis Pharma Deutschland GmbH, Frankfurt, one of the world's foremost pharmaceutical companies. "The FTrees descriptor project is almost complete and this technique is frequently applied at Aventis. We were able to identify interesting new chemical classes in several projects with the FTrees technology", says Karl-Heinz Baringhaus, Head of Computational Chemistry.

The focus of the two year continuation project, now initiated, is the extension of capabilities of BioSolveIT's docking database (DDB). Dr. Christian Lemmen, CEO of BioSolveIT says, "We are excited to be able to extend our collaboration from the ligand-based to the structure-based end of design methodology. Our primary aim is to develop more powerful methodology for discovering lead structures in the often quoted 'haystack of data'". Find out more about past and future goals of this exciting partnership.

As with everything in life, companies grow and develop. Starting off from a small spin off in 2001 and growing into an efficient company providing software technology solutions to both smaller biotechs and big pharma, BioSolveIT has been given a new look.

Our Director Sales & Marketing, Mr. Richard Kidd, goes into more detail about the motivation behind the new design and how we are implementing this new corporate identity.

As detailed in our previous newsletter, in this new section we are focussing on aspects of FlexX that have not been considered to be problems, yet we see them as important points worth addressing for you.

In this issue we take a closer look at protonation in the active site. Protonation states for docking experiments are often uncertain because X-ray crystallography usually does not provide enough details about the protons. Apart from that, the orientation of side-chains of a couple of amino acids is frequently wrong, since their electron densities can not unambiguously be assigned and further information is lacking.
From the chemistry viewpoint, it is obvious that the protonation state has a strong influence its interaction properties. What has previously been a hydrogen-bond donor will possibly become an acceptor when deprotonated; also, previously charged groups will possibly be neutralised – and vice versa. Also the orientation of Hydrogens has a strong influence in that it determines the geometry of potential H-bonds. If un-assessed, these effects may drastically distort your docking and screening results. We strongly recommend to carefully check and prepare your rdf-file – this is where proper assignments have to be made.

If you have any questions or know of any tips and tricks yourself which you would like to share with the FlexX user community, we would appreciate your input at FlexX@BioSolveIT.de.

Workshop 2004
Together with our distribution partner Tripos, Inc. this year we are carrying out the second FlexX Docking Workshop. The workshop is taking place between 18 and 20 August in Princeton, New Jersey. For further information visit our website or simply send us an email with your request.

Availability of talks from ACS and Sheffield
March and April meant a fair bit of travelling for certain BioSolveIT colleagues, who found themselves attending both the ACS National Meeting in Anaheim, USA (talk 1, talk 2), at the end of March/beginning April and then subsequently the Joint Sheffield Conference on Chemo-informatics (talk) in Sheffield, England. The talks given can be found in the conferences section of our website.

Conference Calendar
What's coming up? Our conferences section details some of the more important events we shall be attending later this quarter and in subsequent months, among which you will find our CEO, Dr. Christian Lemmen giving a detailed account of FlexX 2.0 at the fall ACS in Philadelphia (abstract 1, abstract 2).

Identification of Compounds with Nanomolar Binding Affinity for Checkpoint Kinase-1 Using Knowledge-Based Virtual Screening
Paul D. Lyne, Peter W. Kenny, David A. Cosgrove, Chun Deng, Sonya Zabludoff, John J. Wendoloski, and Susan Ashwell
J. Med. Chem. 2004, 47, 1962-1968
details here

Identifying the binding mode of a molecular scaffold
Doron Chema, Doron Eren, Avner Yayon, Amiram Goldblum, and Andrea Zaliani
J. Comput. Aided. Mol. Des. 2004, 18, 23-40
details here

Automated Drawing of Structural Molecular Formulas under Constraints
Patrick Fricker, Marcus Gastreich, and Matthias Rarey
J. Chem. Inf. Comput. Sci. 2004, 44, 1065-78
details here