Dobi K.,Targetex Ltd. |
Hajdu I.,Targetex Ltd. |
Hajdu I.,Hungarian Academy of Sciences |
Flachner B.,Targetex Ltd. |
And 9 more authors.
Molecules | Year: 2014
Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost effective approach. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compound databases but the generated library requires further focusing by various 2D/3D chemoinformatics tools. We report here a combination of the 2D approach with a ligand-based 3D method (Screen3D) which applies flexible matching to align reference and target compounds in a dynamic manner and thus to assess their structural and conformational similarity. In the first case study we compared the 2D and 3D similarity scores on an existing dataset derived from the biological evaluation of a PDE5 focused library. Based on the obtained similarity metrices a fusion score was proposed. The fusion score was applied to refine the 2D similarity search in a second case study where we aimed at selecting and evaluating a PDE4B focused library. The application of this fused 2D/3D similarity measure led to an increase of the hit rate from 8.5% (1st round, 47% inhibition at 10 ìM) to 28.5% (2nd round at 50% inhibition at 10 μM) and the best two hits had 53 nM inhibitory activities. © 2014 by the authors. Source
Englert P.,Eotvos Lorand University |
Kovacs P.,Chemaxon Ltd.
Journal of Chemical Information and Modeling | Year: 2015
Maximum common substructure search is a computationally hard optimization problem with diverse applications in the field of cheminformatics, including similarity search, lead optimization, molecule alignment, and clustering. Most of these applications have strict constraints on running time, so heuristic methods are often preferred. However, the development of an algorithm that is both fast enough and accurate enough for most practical purposes is still a challenge. Moreover, in some applications, the quality of a common substructure depends not only on its size but also on various topological features of the one-to-one atom correspondence it defines. Two state-of-the-art heuristic algorithms for finding maximum common substructures have been implemented at ChemAxon Ltd., and effective heuristics have been developed to improve both their efficiency and the relevance of the atom mappings they provide. The implementations have been thoroughly evaluated and compared with existing solutions (KCOMBU and Indigo). The heuristics have been found to greatly improve the performance and applicability of the algorithms. The purpose of this paper is to introduce the applied methods and present the experimental results. © 2015 American Chemical Society. Source
Kovacs P.,Eotvos Lorand University |
Kovacs P.,Chemaxon Ltd.
Optimization Methods and Software | Year: 2015
An extensive computational analysis of several algorithms for solving the minimum-cost network flow problem is conducted. Some of the considered implementations were developed by the author and are available as part of an open-source C++ optimization library called LEMON (http://lemon.cs.elte.hu/). These codes are compared to other publicly available solvers: CS2, MCF, RelaxIV, PDNET, MCFSimplex, as well as the corresponding components of the IBM ILOG CPLEX Optimization Studio and the LEDA C++ library. This evaluation, to the author's knowledge, is more comprehensive than earlier studies in terms of the range of considered implementations as well as the diversity and size of problem instances. The presented results demonstrate that the primal network simplex and cost-scaling algorithms are the most efficient and robust in general. Other methods, however, can outperform them in particular cases. The network simplex code of the author turned out to be far superior to the other implementations of this method, and it is the most efficient solver on the majority of the considered problem instances. In contrast, the cost-scaling algorithms tend to show better asymptotic behaviour, especially on sparse graphs, and hence they are typically faster than simplex-based methods on huge networks. © 2014 Taylor & Francis. Source
Vass M.,Discovery Chemistry |
Vass M.,VU University Amsterdam |
Jojart B.,University of Szeged |
Bogar F.,Hungarian Academy of Sciences |
And 5 more authors.
Journal of Computer-Aided Molecular Design | Year: 2015
In order to identify molecular models of the human 5-HT6 receptor suitable for virtual screening, homology modeling and membrane-embedded molecular dynamics simulations were performed. Structural requirements for robust enrichment were assessed by an unbiased chemometric analysis of enrichments from retrospective virtual screening studies. The two main structural features affecting enrichment are the outward movement of the second extracellular loop and the formation of a hydrophobic cavity deep in the binding site. These features appear transiently in the trajectories and furthermore the stretches of uniformly high enrichment may only last 4-10 ps. The formation of the inner hydrophobic cavity was also linked to the active-like to inactive-like transition of the receptor, especially the so-called connector region. The best structural models provided significant and robust enrichment over three independent ligand sets. © 2015 Springer International Publishing Switzerland. Source