Topological fuzzy pharmacophore triplets (2D-FPT), using the number of interposed bonds to measure separation between the atoms representing pharmacophore types, were employed to establish and validate quantitative structure-activity relationships (QSAR). Thirteen data sets for which state-of-the-art QSAR models were reported in literature were revisited in order to benchmark 2D-FPT biological activity-explaining propensities. Linear and nonlinear QSAR models were constructed for each compound series (following the original author's splitting into training/validation subsets) with three different 2D-FPT versions, using the genetic algorithm-driven Stochastic QSAR sampler (SQS) to pick relevant triplets and fit their coefficients. 2D-FPT QSARs are computationally cheap, interpretable, and perform well in benchmarking. In a majority of cases (10/13), default 2D-FPT models validated better than or as well as the best among those reported, including 3D overlay-dependent approaches. Most of the analogues series, either unaffected by protonation equilibria or unambiguously adopting expected protonation states, were equally well described by rule-or pK a -based pharmacophore flagging. Thermolysin inhibitors represent a notable exception: pK a -based flagging boosts model quality, althoughssurprisinglysnot due to proteolytic equilibrium effects. The optimal degree of 2D-FPT fuzziness is compound set dependent. This work further confirmed the higher robustness of nonlinear over linear SQS models. In spite of the wealth of studied sets, benchmarking is nevertheless flawed by low intraset diversity: a whole series of thereby caused artifacts were evidenced, implicitly raising questions about the way QSAR studies are conducted nowadays. An in-depth investigation of thrombin inhibition models revealed that some of the selected triplets make sense (one of these stands for a topological pharmacophore covering the P 1 and P 2 binding pockets). Nevertheless, equations were either unable to predict the activity of the structurally different ligands or tended to indiscriminately predict any compound outside the training family to be active. 2D-FPT QSARs do however not depend on any common scaffold required for molecule superimposition and may in principle be trained on hand of diverse sets, which is a must in order to obtain widely applicable models. Adding (assumed) inactives of various families for training enabled discovery of models that specifically recognize the structurally different actives.

We revisit the dynamics of a gene repressed by its own protein in the case where the transcription rate does not adapt instantaneously to protein concentration but is a dynamical variable. We derive analytical criteria for the appearance of sustained oscillations and find that they require degradation mechanisms much less nonlinear than for infinitely fast regulation. Deterministic predictions are confirmed by stochastic simulations of this minimal genetic oscillator.

The chemotaxis and integrin-mediated adhesion of T lymphocytes triggered by secreted cyclophilin B (CypB) depend on interactions with both cell surface heparan sulfate proteoglycans (HSPG) and the extracellular domain of the CD147 membrane receptor. Here, we use NMR spectroscopy to characterize the interaction of CypB with heparin-derived oligosaccharides. Chemical shift perturbation experiments allowed the precise definition of the heparan sulfate (HS) binding site of CypB. The N-terminal extremity of CypB, which contains a consensus sequence for heparin-binding proteins was modeled on the basis of our experimental NMR data. Because the HS binding site extends toward the CypB catalytic pocket, we measured its peptidyl-prolyl cis-trans isomerase (PPIase) activity in the absence or presence of a HS oligosaccharide toward a CD147-derived peptide. We report the first direct evidence that CypB is enzymatically active on CD147, as it is able to accelerate the cis/trans isomerization of the Asp 179 -Pro 180 bond in a CD147-derived peptide. However, HS binding has no significant influence on this PPIase activity. We thus conclude that the glycanic moiety of HSPG serves as anchor for CypB at the cell surface, and that the signal could be transduced by CypB via its PPIase activity toward CD147.First characterized as the molecular targets of the immunosuppressive drug cyclosporin A (CsA), 3 cyclophilins (Cyps) constitute one class of the prolyl cis/trans isomerases that catalyze the cis/trans interconversion of the peptide bond preceding a proline (1, 2). Members of this class such as the predominantly cytoplasmic CypA, the secreted CypB, and the mitochondrial CypD are small ubiquitous proteins sharing a high sequence homology (65% identity between human CypA and CypB), that translates into a closely related three-dimensional fold. Indeed, the NMR and crystal structures of CypA free and in complex with CsA (3-6), as well as the crystal structure of CypB in complex with a cyclosporine analogue (7) all show the same core structure composed of eight antiparallel ␤-strands forming a ␤-barrel surrounded by ␣-helices and loops. Whereas the nearly identical active site and CsA binding pocket further underscore their close relationship, both proteins do differ in their N and C termini, CypB containing two peptides of some 10 residues long that are lacking in CypA.CypA and CypB act in the progression of inflammatory diseases such as rheumatoid arthritis and psoriasis, but are equally involved in the first steps of certain viral infections (8 -10). Their inflammatory activity is conditioned by their interaction with heparan sulfate proteoglycans (HSPGs) and the membrane receptor CD147, two binding partners at the cell surface of T cell lymphocytes, granulocytes and macrophages (11-14). Significantly, both molecular partners have equally been described as co-receptors for the HIV-1 virus (10,12,15).Both intact prolyl cis/trans activity of the cyclophilins and the presence of the Pro 180 residue of CD147, located on one of the two ex...