ACS Denver 2015: Alignment of diverse ligands for a protein: a solved problem?

There are many methods available to align ligands in 3D in the absence of protein information. However, they fall into three main classes: atom matching/pharmacophore-based methods (GALAHAD, Open3DALIGN, Align-it), shape/electrostatics-based methods (Cresset, ROCS, Phase Shape, ShaEP) and QM potential-derived methods (CosmoSim3D). Each of these methods has different strengths and weaknesses. We have tested representatives of…

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ACS Denver 2015: Scaffold hopping: Balancing novelty, accessibility and physico-chemical properties

Scaffold hopping remains a central task in medicinal chemistry for generating and protecting intellectual property. We have previously presented a technique for rapidly generating reasonable yet novel scaffold replacements using molecular fields which has been extended to include R-group replacement. The approach uses a database of molecule fragments or available reagents to suggest replacements that…

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March 2015 newsletter

A 3D-QSAR study on DPP-4 inhibitors In this case study, Giovanna Tedesco describes how a robust 3D-QSAR (Quantitative Structure Activity Relationship) model was built for a data set of 73 dipeptidyl peptidase IV (DPP-4, a serine protease) inhibitors using Forge, Cresset’s powerful ligand-focused workbench for understanding SAR and design. Ad hoc Forge 3D display capabilities…

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Using Cresset’s Spark to grow and link distant fragment hits with sensible chemistry

Abstract The main advantage of fragment-based drug discovery (FBDD) is that the starting point, despite having weak potency, often has high efficiency of interaction with biological target. Optimization of the fragment by adding atoms ideally preserves this initial efficiency, to yield a tractable lead with superior properties. One potential pitfall is that modern hit optimization…

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The three secrets to great 3D-QSAR: Alignment, alignment and alignment

In this blog post I’m going to look at 3D-QSAR in Cresset’s software. I will share some of my experience on the best way to do it and, more importantly, what not to do. 3D-QSAR is one of those techniques that everybody loves. When it’s done well you get quantitative results, validation that the model…

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