Unraveling principles of lead discovery: from unfrustrated energy landscapes to novel molecular anchors.

The search for novel leads is a critical step in the drug discovery process. Computational approaches to identify new lead molecules have focused on discovering complete ligands by evaluating the binding affinity of a large number of candidates, a task of considerable complexity. A new computational method is introduced in this work based on the premise that the primary molecular recognition event in the protein binding site may be accomplished by small core fragments that serve as molecular anchors, providing a structurally stable platform that can be subsequently tailored into complete ligands. To fulfill its role, we show that an effective molecular anchor must meet both the thermodynamic requirement of relative energetic stability of a single binding mode and its consistent kinetic accessibility, which may be measured by the structural consensus of multiple docking simulations. From a large number of candidates, this technique is able to identify known core fragments responsible for primary recognition by the FK506 binding protein (FKBP-12), along with a diverse repertoire of novel molecular cores. By contrast, absolute energetic criteria for selecting molecular anchors are found to be promiscuous. A relationship between a minimum frustration principle of binding energy landscapes and receptor-specific molecular anchors in their role as "recognition nuclei" is established, thereby unraveling a mechanism of lead discovery and providing a practical route to receptor-biased computational combinatorial chemistry.

Principles of protein-protein interactions.

This review examines protein complexes in the Brookhaven Protein Databank to gain a better understanding of the principles governing the interactions involved in protein-protein recognition. The factors that influence the formation of protein-protein complexes are explored in four different types of protein-protein complexes--homodimeric proteins, heterodimeric proteins, enzyme-inhibitor complexes, and antibody-protein complexes. The comparison between the complexes highlights differences that reflect their biological roles.

Robotic control systems based on bioinspired multi-agent systems: application of the principles of neuroscience to robotics

Robotics is a field that presents a large number of problems because it depends on a large number of disciplines, devices, technologies and tasks. Its expansion from perfectly controlled industrial environments toward open and dynamic environment presents a many new challenges, such as robots household robots or professional robots. To facilitate the rapid development of robotic systems, low cost, reusability of code, its medium and long term maintainability and robustness are required novel approaches to provide generic models and software systems who develop paradigms capable of solving these problems. For this purpose, in this paper we propose a model based on multi-agent systems inspired by the human nervous system able to transfer the control characteristics of the biological system and able to take advantage of the best properties of distributed software systems.

Principles of a Two-Tier European Deposit (Re-)Insurance System. CEPS Policy Brief No. 287, 17 April 2013.

There is general agreement that banking supervision and resolution have to be organised at the same level. It is often argued, however, that there is no need to tackle deposit insurance because it is too politically sensitive. This note proposes to apply the principles of subsidiarity and re-insurance to deposit insurance: Existing national deposit guarantee schemes (DGSs) would continue to operate much as before (with only minimal standards set by an EU directive), but they would be required to take out re-insurance against risks that would be too large to be covered by them. A European Reinsurance Fund (EReIF) would provide this reinsurance financed by premia paid by the national DGSs, just as any reinsurance company does in the private sector. The European Fund would pay out only in case of large losses. This ‘deductible’ would provide the national authorities with the proper incentives, but the reinsurance cover would stabilize depositor confidence even in the case of large shocks. Ideally the national DGSs would be responsible also for resolution. Experience has shown banking systems are more stable if deposit insurers are also responsible for resolution. The approach proposed here could thus be also used to design the ‘Single Resolution Mechanism’ (SRM) which is being discussed as a complement to the ‘Single Supervisory Mechanism’ (SSM). It will of course take time to build up the funding for such a reinsurance fund. This approach is thus not meant to deal with legacy problems from the current crisis.

European Criminal Law and General Principles of Union Law. Research Papers in Law, 5/2005

From the Introduction. The European Court of Justice, partly followed in this by the European legislator, has regulated Community law and policy through a set of general principles of law. For the Community legal order in the first pillar, general legal principles have developed from functional policy areas such as the internal market, the customs union, the monetary union, the common agricultural policy, the European competition policy, etc., which are of great importance for the quality and legitimacy of Community law. The principles in question are not so much general legal principles of an institutional character, such as the priority of Community law, direct effect or Community loyalty, but rather principles of law which shape the fundamental rights and basic rights of the citizen. I refer to the principle of legality, of nulla poena, the inviolability of the home, the nemo tenetur principle, due process, the rights of the defence, etc. Many of these legal principles have been elevated to primary Community law status by the European Court of Justice, often as a result of preliminary questions. Nevertheless, a considerable number of them have also been elaborated in the context of contentious proceedings before the Court of Justice, such as in the framework of European competition law and European public servants law.

Decentralisation of EC Competition Law Enforcement and General Principles of Community Law. Research Papers in Law, 4/2004

From the Introduction. By virtue of Council Regulation No. 1/2003, as of 1st May 2004 the full application of EC competition law will be entrusted to national competition authorities (hereinafter NCAs) and national courts. The bold reform of EC competition law enforcement adheres to the system of executive federalism1 which characterises the EC legal system. The repartition of competences within the Community allocates implementation of Community law mainly at Member States level. Pursuant to Article 10 EC, they are responsible for the implementation of the measures which have been adopted at Community level for the achievement of the objectives specified in the EC Treaty. Consequently, the attainment of the Community objectives depends very much upon the cooperation of national authorities, which act in accordance with their own national procedural rules.2 The various national procedural rules present themselves as conduits through which Community law is implemented and enforced. While as a rule Community law is not designed to alter national procedural rules, the Community legal order cannot afford to leave national procedural rules untouched when they are liable to hamper the effective application of Community law....For reason of space, this contribution intends only to highlight some aspects of Regulation No. 1/2003 with regard to which general principles of Community law are able to condition national procedural rules.

General Principles of EU Law: The Ghost in the Platonic Heaven in Need of Conceptual Clarification. Pittsburgh Papers on the European Union Vol. 2, 2013

General principles are en vogue in EU law – and in need of conceptual clarification. A closer look at several concepts of principle in legal philosophy and legal theory sheds light upon the concept of general principles in EU law. A distinction between an aprioristic model of principle and a model of principle informed by legal positivism may contribute to clarifying the genesis of a (general) principle in EU law, as well as its nature and functions. This paper demonstrates that an evolution has taken place from a reliance on seemingly natural law inspired reflections of general principles via the desperate search to ground general principles in various kinds of sources based on a more or less sound methodology towards an increasing reliance on strictly positivistic approaches. Against this backdrop, general principles are likely to lose significance where there are other norms while retaining an important yet uncontrollable role where the traditional canon of sources is silent.