Drug attrition late in preclinical or clinical development is a serious economic problem in the field of drug discovery. These problems can be linked, in part, to the quality of the compound collections used during the hit generation stage and to the selection of compounds undergoing optimization. Here, we present FAF-Drugs3, a web server that can be used for drug discovery and chemical biology projects to help in preparing compound libraries and to assist decision-making during the hit selection/lead optimization phase. Since it was first described in 2006, FAF-Drugs has been significantly modified. The tool now applies an enhanced structure curation procedure, can filter or analyze molecules with user-defined or eight predefined physicochemical filters as well as with several simple ADMET (absorption, distribution, metabolism, excretion and toxicity) rules. In addition, compounds can be filtered using an updated list of 154 hand-curated structural alerts while Pan Assay Interference compounds (PAINS) and other, generally unwanted groups are also investigated. FAF-Drugs3 offers access to user-friendly html result pages and the possibility to download all computed data. The server requires as input an SDF file of the compounds; it is open to all users and can be accessed without registration at http://fafdrugs3.mti.univ-paris-diderot.fr.

The anticoagulant protein C system regulates the activity of coagulation factors VIIIa and Va, cofactors in the activation of factor X and prothrombin, respectively. Protein C is activated on endothelium by the thrombin-thrombomodulin-EPCR (endothelial protein C receptor) complex. Activated protein C (APC)-mediated cleavages of factors VIIIa and Va occur on negatively charged phospholipid membranes and involve protein cofactors, protein S and factor V. APC also has anti-inflammatory and anti-apoptotic activities that involve binding of APC to EPCR and cleavage of PAR-1 (protease-activated receptor-1). Genetic defects affecting the protein C system are the most common risk factors of venous thrombosis. The protein C system contains multi-domain proteins, the molecular recognition of which will be reviewed.

Despite recent studies, the organization of coagulation factor VIII (FVIII) on a phospholipid (PL) membrane is not known in detail. Thus, 2-dimensional (2D) crystals of human FVIII lacking the B domain were prepared for electron microscopy onto negatively charged PL monolayers. The 3-dimensional (3D) density map of the PL-bound FVIII protein was calculated at 1.5 nm. Existing atomic data and models for FVIII domains were fitted unambiguously within the 3D density map of the molecule. FVIII domains arrangement followed a compact spiral organization with the A3 domains in close association with the C1 and C2 domains near the PL surface. Viewed toward the membrane the A domains' heterotrimer is oriented side-on with the pseudo-3-fold axis almost parallel to the PL surface and A1 fully covering C1. The C2 domain is partially overlapped by the A2 domain of an adjacent molecule in the 2D crystal, favoring close packing. Viewed parallel to the membrane, C2 is slightly inclined to the PL surface covering an area of 12 nm 2 . Four C2 loops are embedded within the lipid monolayer at about 0.7 to 1.0 nm depth. C1 forms almost a right angle with C2, its long axis nearly parallel to the membrane. The proposed structure for membrane-bound FVIII results from modeling of the FVIII domains within a 3D density map obtained from electron crystallography and accords with the main biochemical and structural information known to date. A model is proposed for FVIIIa and factor IXa assembly within the membrane-bound factor X-activating complex. IntroductionFactor VIII (FVIII) is a plasma protein essential for blood coagulation and is deficient or defective in individuals with hemophilia A. FVIII is synthesized as a 300-kd precursor protein with domain structure A1-A2-B-A3-C1-C2. 1,2 In plasma it circulates as a series of noncovalently bound heterodimers, produced by proteolytic cleavage at the B-A3 junction or within the B domain. 3 Thus, FVIII in vivo consists of a heavy chain (HC) of variable molecular mass (from 90 kd, when only the A1-A2 domains are present, to 220 kd when the full-length B domain is present) and a light chain (A3-C1-C2; LC) of 76 kd molecular mass (for a review, see Lenting et al 4 ).In the process of blood coagulation, FVIII acts as a cofactor to the serine protease factor IXa (FIXa). Before the initiation of coagulation, FVIII circulates in a noncovalent complex with von Willebrand factor (VWF). Limited proteolysis near the N-terminus of LC by traces of thrombin removes a peptide containing a VWF-binding site, resulting in release of free FVIII. Further proteolysis between the A1 and A2 domains results in generation of FVIIIa, the active heterotrimeric cofactor. Binding of FVIIIa to negatively charged phospholipid (PL) and to factor IXa (FIXa) form the factor X-ase (FX-ase) complex. The product of the reaction, activated factor X (FXa), forms with activated factor V (cofactor FVa) a similar membrane-bound system, the prothrombinase complex that converts prothrombin to thrombin. 6 The serine proteases FIXa and F...

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Supplementary data are available at Bioinformatics online.

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Background: Drug discovery and chemical biology are exceedingly complex and demanding enterprises. In recent years there are been increasing awareness about the importance of predicting/optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of small chemical compounds along the search process rather than at the final stages. Fast methods for evaluating ADMET properties of small molecules often involve applying a set of simple empirical rules (educated guesses) and as such, compound collections' property profiling can be performed in silico. Clearly, these rules cannot assess the full complexity of the human body but can provide valuable information and assist decision-making.