Evolutionary Computation and QSAR Research

[Abstract] The successful high throughput screening of molecule libraries for a specific biological property is one of the main improvements in drug discovery. The virtual molecular filtering and screening relies greatly on quantitative structure-activity relationship (QSAR) analysis, a mathematical model that correlates the activity of a molecule with molecular descriptors. QSAR models have the potential to reduce the costly failure of drug candidates in advanced (clinical) stages by filtering combinatorial libraries, eliminating candidates with a predicted toxic effect and poor pharmacokinetic profiles, and reducing the number of experiments. To obtain a predictive and reliable QSAR model, scientists use methods from various fields such as molecular modeling, pattern recognition, machine learning or artificial intelligence. QSAR modeling relies on three main steps: molecular structure codification into molecular descriptors, selection of relevant variables in the context of the analyzed activity, and search of the optimal mathematical model that correlates the molecular descriptors with a specific activity. Since a variety of techniques from statistics and artificial intelligence can aid variable selection and model building steps, this review focuses on the evolutionary computation methods supporting these tasks. Thus, this review explains the basic of the genetic algorithms and genetic programming as evolutionary computation approaches, the selection methods for high-dimensional data in QSAR, the methods to build QSAR models, the current evolutionary feature selection methods and applications in QSAR and the future trend on the joint or multi-task feature selection methods.Instituto de Salud Carlos III, PIO52048Instituto de Salud Carlos III, RD07/0067/0005Ministerio de Industria, Comercio y Turismo; TSI-020110-2009-53)Galicia. Consellería de Economía e Industria; 10SIN105004P

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

TOWARDS INSTITUTIONAL INFRASTRUCTURES FOR E-SCIENCE: The Scope of the Challenge

The three-fold purpose of this Report to the Joint Information Systems Committee (JISC) of the Research Councils (UK) is to: • articulate the nature and significance of the non-technological issues that will bear on the practical effectiveness of the hardware and software infrastructures that are being created to enable collaborations in e- Science; • characterise succinctly the fundamental sources of the organisational and institutional challenges that need to be addressed in regard to defining terms, rights and responsibilities of the collaborating parties, and to illustrate these by reference to the limited experience gained to date in regard to intellectual property, liability, privacy, and security and competition policy issues affecting scientific research organisations; and • propose approaches for arriving at institutional mechanisms whose establishment would generate workable, specific arrangements facilitating collaboration in e-Science; and, that also might serve to meet similar needs in other spheres such as e- Learning, e-Government, e-Commerce, e-Healthcare. In carrying out these tasks, the report examines developments in enhanced computer-mediated telecommunication networks and digital information technologies, and recent advances in technologies of collaboration. It considers the economic and legal aspects of scientific collaboration, with attention to interactions between formal contracting and 'private ordering' arrangements that rest upon research community norms. It offers definitions of e-Science, virtual laboratories, collaboratories, and develops a taxonomy of collaborative e-Science activities which is implemented to classify British e-Science pilot projects and contrast these with US collaboratory projects funded during the 1990s. The approach to facilitating inter-organizational participation in collaborative projects rests upon the development of a modular structure of contractual clauses that permit flexibility and experience-based learning.

The early history and emergence of molecular functions and modular scale-free network behavior

The formation of protein structural domains requires that biochemical functions, defined by conserved amino acid sequence motifs, be embedded into a structural scaffold. Here we trace domain history onto a bipartite network of elementary functional loop (EFL) sequences and domain structures defined at the fold superfamily (FSF) level of Structural Classification of Proteins (SCOP). The resulting ‘elementary functionome’ network and its EFL and FSF graph projections unfold evolutionary ‘waterfalls’ describing emergence of primordial functions. Waterfalls reveal how ancient EFLs are shared by FSF structures in two initial waves of functional innovation that involve founder ‘p-loop’ and ‘winged helix’ domain structures. They also uncover a dynamics of modular motif embedding in domain structures that is ongoing, which transfers ‘preferential’ cooption properties of ancient EFLs to emerging FSFs. Remarkably, we find that the emergence of molecular functions induces hierarchical modularity and power law behavior in network evolution as the networks of motifs and structures expand metabolic pathways and translation