Zoltán Boldizsár Simon

Contribution of 2D and 3D structural features of drug molecules in the prediction of Drug Profile Matching.

Drug Profile Matching (DPM), a novel virtual affinity fingerprinting method capable of predicting the medical effect profiles of small molecules, was introduced by our group recently. The method exploits the information content of interaction patterns generated by flexible docking to a series of rigidly kept nontarget protein active sites. We presented the ability of DPM to classify molecules excellently, and the question arose, what the contribution of 2D and 3D structural features of the small molecules is to the intriguingly high prediction power of DPM. The present study compared the prediction powers for effect profiles of 1163 FDA-approved drug compounds determined by DPM and ChemAxon 2D and 3D similarity fingerprinting approaches. We found that DPM outperformed the 2D and 3D approaches in almost all therapeutic categories for drug classification except for mechanically rigid structural categories where high accuracy was obtained by all three methods. Moreover, we also tested the predictive power of DPM on external data by reducing the parent data set and demonstrated that DPM can overcome the common screening problems of 2D and 3D similarity methods arising from the presence of structurally diverse molecules in certain effect categories.

Virtual Affinity Fingerprints for Target Fishing: A New Application of Drug Profile Matching

We recently introduced Drug Profile Matching (DPM), a novel virtual affinity fingerprinting bioactivity prediction method. DPM is based on the docking profiles of ca. 1200 FDA-approved small-molecule drugs against a set of nontarget proteins and creates bioactivity predictions based on this pattern. The effectiveness of this approach was previously demonstrated for therapeutic effect prediction of drug molecules. In the current work, we investigated the applicability of DPM for target fishing, i.e. for the prediction of biological targets for compounds. Predictions were made for 77 targets, and their accuracy was measured by Receiver Operating Characteristic (ROC) analysis. Robustness was tested by a rigorous 10-fold cross-validation procedure. This procedure identified targets (N = 45) with high reliability based on DPM performance. These 45 categories were used in a subsequent study which aimed at predicting the off-target profiles of currently approved FDA drugs. In this data set, 79% of the known drug-target interactions were correctly predicted by DPM, and additionally 1074 new drug-target interactions were suggested. We focused our further investigation on the suggested interactions of antipsychotic molecules and confirmed several interactions by a review of the literature.

Thermodynamic Analysis Reveals Structural Rearrangement during the Acylation Step in Human Trypsin 4 on 4-Methylumbelliferyl 4-Guanidinobenzoate Substrate Analogue

Human trypsin 4 is an unconventional serine protease that possesses an arginine at position 193 in place of the highly conserved glycine. Although this single amino acid substitution does not affect steady-state activity on small synthetic substrates, it has dramatic effects on zymogen activation, interaction with canonical inhibitors, and substrate specificity toward macromolecular substrates. To study the effect of a non-glycine residue at position 193 on the mechanism of the individual enzymatic reaction steps, we expressed wild type human trypsin 4 and its R193G mutant. 4-Methylumbelliferyl 4-guanidinobenzoate has been chosen as a substrate analogue, where deacylation is rate-limiting, and transient kinetic methods were used to monitor the reactions. This experimental system allows for the separation of the individual reaction steps during substrate hydrolysis and the determination of their rate constants dependably. We suggest a refined model for the reaction mechanism, in which acylation is preceded by the reversible formation of the first tetrahedral intermediate. Furthermore, the thermodynamics of these steps were also investigated. The formation of the first tetrahedral intermediate is highly exothermic and accompanied by a large entropy decrease for the wild type enzyme, whereas the signs of the enthalpy and entropy changes are opposite and smaller for the R193G mutant. This difference in the energetic profiles indicates much more extended structural and/or dynamic rearrangements in the equilibrium step of the first tetrahedral intermediate formation in wild type human trypsin 4 than in the R193G mutant enzyme, which may contribute to the biological function of this protease.

Why the Anthropocene Has No History: Facing the Unprecedented

This paper argues that the tendency to invoke modern historical thinking in trying to make sense of the Anthropocene amounts to an untenable, self-contradictory, and self-defeating enterprise. There is a fundamental contradiction between the prospect of unprecedented change as entailed by the Anthropocene and the deep continuity of a processual historical change. On the one hand, conceiving the Anthropocene as the prospect of the unprecedented creates a demand for immediate action to prevent future catastrophe. On the other hand, pointing out the inequalities in the historical process of bringing about the Anthropocene creates a demand for social justice. Although both are legitimate and important demands, they are incompatible. They represent different temporalities, different conceptions of change, and different modes of action. Inasmuch as the Anthropocene appears as unprecedented, it does not have a processual history; and inasmuch as it has a processual history, it is not the Anthropocene.

History set into motion again

It is believed to be common knowledge that history (in the sense of things done, in the sense of a collective singular) is suspended, that history is doomed to remain motionless. What is more, we all – or at least many of us – tend to believe that this precisely is how it should be: history, if such thing exists at all, has to stand still. It is against this backdrop that I wish to point out that there is a cultural phenomenon we should not leave unnoticed, namely, that a new quasi-substantive philosophy of history – operating with the notions of commemoration, trauma, and the sublime – sets history into motion again. It sets history into motion by reclaiming the monstrosities of the world, that is, by compensating for the rather one-sided attention paid to language in the last decades; and it sets history into motion despite the respect it seriously pays to the primary suspension of history.

Identification of PPARγ ligands with One-dimensional Drug Profile Matching.

Introduction Computational molecular database screening helps to decrease the time and resources needed for drug development. Reintroduction of generic drugs by second medical use patents also contributes to cheaper and faster drug development processes. We screened, in silico, the Food and Drug Administration-approved generic drug database by means of the One-dimensional Drug Profile Matching (oDPM) method in order to find potential peroxisome proliferator-activated receptor gamma (PPARγ) agonists. The PPARγ action of the selected generics was also investigated by in vitro and in vivo experiments. Materials and methods The in silico oDPM method was used to determine the binding potency of 1,255 generics to 149 proteins collected. In vitro PPARγ activation was determined by measuring fatty acid-binding protein 4/adipocyte protein gene expression in a Mono Mac 6 cell line. The in vivo insulin sensitizing effect of the selected compound (nitazoxanide; 50–200 mg/kg/day over 8 days; n = 8) was established in type 2 diabetic rats by hyperinsulinemic euglycemic glucose clamping. Results After examining the closest neighbors of each of the reference set’s members and counting their most abundant neighbors, ten generic drugs were selected with oDPM. Among them, four enhanced fatty acid-binding protein/adipocyte protein gene expression in the Mono Mac 6 cell line, but only bromfenac and nitazoxanide showed dose-dependent actions. Induction by nitazoxanide was higher than by bromfenac. Nitazoxanide lowered fasting blood glucose levels and improved insulin sensitivity in type 2 diabetic rats. Conclusion We demonstrated that the oDPM method can predict previously unknown therapeutic effects of generic drugs. Nitazoxanide can be the prototype chemical structure of the new generation of insulin sensitizers.

The Impossibility of) Acting Upon a Story That We Can Believe

Abstract The historical sensibility of Western modernity is best captured by the phrase ‘acting upon a story that we can believe’. Whereas the most famous stories of historians facilitated nation-building processes, philosophers of history told the largest possible story to act upon: history itself. When the rise of an overwhelming postwar skepticism about the modern idea of history discredited the entire enterprise, the historical sensibility of ‘acting upon a story that we can believe’ broke apart into its constituents: action, story form, and belief in a feasible future outcome. Its constituent parts nevertheless still exist, either separately or in paired arrangements. First, believable stories are still told, but without an equally believable future outcome. Second, there still exists a feasible vision of a future (in the shape of what I call the prospect of unprecedented change, especially in prospects of technology and the Anthropocene), but this defies story form. And third, it is even possible to act upon that feasible future, but such action aims at avoiding worst-case scenarios instead of facilitating best outcomes. These, I believe, are the features of an emerging postwar historical sensibility that the theory and philosophy of history has yet to understand.

Modeling Polypharmacological Profiles by Affinity Fingerprinting.

Single target based approaches often proved to be unsuccessful in complex multigenic diseases such as cancer or schizophrenia. Multi-target drugs can be more efficacious in this regard by modulating multiple processes in the organism. According to the theory of polypharmacology, bioactive molecules possess characteristic interaction patterns that are responsible for their effects and side-effects and getting acquainted with this typical profile is increasingly desired to promote pharmaceutical research and development. There is a novel way of approaching polypharmacology that takes into account the interaction of molecules to a set of proteins that are not necessarily known biological targets of the compounds. Applying a carefully selected panel of proteins that can model the possible interactions a molecule can exert when administered to a human body, holds out a promise of biological activity prediction. This review aims to summarize a number of such bioactivity profiling-based approaches set up recently and present their application areas within the drug discovery field.

We Are History: The Outlines of a Quasi-Substantive Philosophy of History

Abstract In times of a felt need to justify the value of the humanities, the need to revisit and re-establish the public relevance of the discipline of history cannot come as a surprise. On the following pages I will argue that this need is unappeasable by scholarly proposals. The much desired revitalization of historical writing lies instead in reconciling ourselves with the dual meaning of the word history, in exploring the necessary interconnection between history understood as the course of events and as historical writing. Despite the general tendency of the last decades to forbid philosophizing about history in the former sense (at least in departments of history and philosophy), I think that to a certain extent we already do so without succumbing to substantive thought. We already have the sprouts of a speculative although only quasi-substantive philosophy of history that nevertheless takes seriously the postwar criticism of the substantive enterprise. In this essay I will first try to outline this quasi-substantive philosophy of history that attests to the historical sensibility of our times; and second, I will try to outline its consequences regarding history as historical writing. Finally, in place of a conclusion I will suggest that historical writing is not as much a contribution to public agendas as it is the very arena in which public life is at stake.

Experience as the Invisible Drive of Historical Writing

Abstract From time to time our tiny intellectual worlds are simultaneously shaken by big ideas – ideas that, however big they are, have their expiration-date. Such is the case with the idea of the impossibility to find life outside language. In this essay, I picture what I think is the current state of the philosophy of history after the so-called linguistic turn and what I think the direction is where the philosophy of history might be headed by taking into account the important job done by linguistic theories. I regard the abandonment of epistemology and the arrival to the realm of aesthetics as a point of no return, and conclude that a new philosophy of history has to have an aesthetic character. However, due to the omnipotence of language I also detect a narrow constructive potential in linguistic theories and argue that a new philosophy of history has to have the dual task of searching for life outside language while remaining in the realm of aesthetics. As a next step, I identify Frank Ankersmit’s notion of an individual historical experience as a move towards the fulfillment of this dual task. Finally, because Ankersmit’s experience remains mute, in the second half of the essay I attempt to present an outline of the possibility of a fruitful cooperation between the philosophy of history and phenomenology. More precisely, I am trying to synchronize Ankersmit’s notion of an individual historical experience with Laszlo Tengelyi’s phenomenological experiments with experience and let Tengelyi speak where Ankersmit “stops talking”. As a result, with the help of Tengelyi, an aperture can be found in language through which experience might worm its way. Due to this fissure, experience might be regarded as an invisible driving force behind linguistic expressions, and thus behind historical writing.