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Ravitz O.,SimBioSys Inc.
Drug Discovery Today: Technologies | Year: 2013

Enabled by an increasing body of electronically available experimental data and by advances in computer hardware and software, new technologies are emerging that are designed to support the creativity of chemists during synthesis planning. Leading this development are innovative synthetic route prediction tools that are designed to suggest new reactions and paths to target molecules as an idea-generating engine. Other tools are using known reactions in a combinatorial fashion to suggest new routes that are cost-optimized or satisfy some other global criteria. We review the latest developments and the main tools in this domain. © 2012 Elsevier Ltd. All rights reserved.

There are numerous methods for flexible ligand docking, including stochastic and systematic methods to sample the conformational and pose space of the ligand. The eHiTS docking engine described in this chapter uses a fragment-based approach closely resembling the experimental fragment-based design techniques that flood the active site cavity with small binding fragments independently from each other and then look for ways to link up the fragments. eHiTS is a deterministic, exhaustive flexible docking method that systematically covers the part of the conformational and positional search space that avoids severe steric clashes, producing highly accurate docking poses at a speed practical for virtual high throughput screening. A new scoring function has been developed as part of the eHiTS flexible ligand docking software. The method has a unique approach to combine the strengths of the statistical and empricial scoring functions. Statistical information was collected from a large number of crystal structures considering the full distribution of interaction geometries as described by the temperature factors associated with every atom in the crystal structrues. Empricial functions are derived from the statistical data to define the final scoring function terms. © 2011 American Chemical Society.

Ravitz O.,SimBioSys Inc. | Zsoldos Z.,SimBioSys Inc. | Simon A.,SimBioSys Inc.
Journal of Computer-Aided Molecular Design | Year: 2011

We present three complementary approaches for score-tuning that improve docking performance in pose prediction, virtual screening and binding affinity assessment. The methodology utilizes experimental data to customize the scoring function for the system of interest considering the specific docking scenario. The tuning approach, which has been implemented as an automated utility in eHiTS, is introduced as a solution to one of the conundrums of the molecular docking paradigm, namely, the lack of a universally well performing scoring function. The accuracy of scoring functions has been shown to be generally system-dependent, and particularly lacking for binding energy and bio-activity predictions. In the proposed approach, pose and energy predictions are enhanced by adjusting the relative weights of the eHiTS energy terms to improve score-RMSD or score-affinity correlations. In a virtual screening context ligand-based similarity is used to rescale the docking score such that better enrichment factors are achieved. We discuss the algorithmic details of the methods, and demonstrate the effects of score tuning on a variety of targets, including CDK2, BACE1 and neuraminidase, as well as on the popular benchmarks-the Directory of Useful Decoys and the PDBBind database. © 2011 Springer Science+Business Media B.V.

Cook A.,University of Leeds | Johnson A.P.,University of Leeds | Law J.,SimBioSys Inc. | Mirzazadeh M.,SimBioSys Inc. | And 2 more authors.
Wiley Interdisciplinary Reviews: Computational Molecular Science | Year: 2012

The discipline of retrosynthetic analysis is now just over 40 years old. From the earliest day, attempts were made to incorporate this approach into computer programs to test the extent in which chemical perception and synthetic thinking could be formalized. Despite pioneering research efforts, computer-aided synthetic analysis failed to achieve widespread routine use by chemists, which can be attributed in part to the difficulty of building the required high-quality retrosynthetic transform databases required for credible analyses. However, with the advent over the past 25 years of large comprehensive reaction databases, work on successfully automating the construction of reliable and comprehensive reaction rule databases is promising to revitalize research in this field. This review compares and contrasts the diverse approaches taken by selected programs in both the design and implementation of molecule feature perception and reaction rule representation, and we review the concepts of synthetic strategy selection, representation, and execution. In particular, we discuss the current work on automating the construction of reliable and comprehensive synthetic rule sets from available reaction databases in newer programs such as ARChem. We argue that the progress achieved in this aspect paves the way to a deeper exploration of computer approaches to applying strategy and control in the synthesis problem. © 2011 John Wiley & Sons, Ltd.

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