Predicting regioselectivity and lability of P450 metabolism
This article describes the underlying methods, validation and example applications of the most recent models of Cytochrome P450 metabolism in…
Extrapolative prediction using physically-based QSAR
Surflex-QMOD integrates chemical structure and activity data to produce physically-realistic models for binding affinity prediction.
The challenges of making decisions using uncertain data
This peer-reviewed paper discusses the challenges of using uncertain experimental data to make confident decisions on the selection of compounds.…
Knowledge-guided docking: accurate prospective prediction of bound configurations of novel ligands using Surflex-Dock
We present an approach that uses structural information known prior to a particular cutoff-date to make predictions on ligands whose bounds structures were determined later. The knowledge-guided docking protocol was tested on a set of ten protein targets using a total of 949 ligands.
Breaking free from chemical spreadsheets
This article explores the benefits of a more intuitive and flexible approach to viewing and interacting with drug discovery data,…
Chemical and protein structural basis for biological crosstalk between PPARα and COX enzymes
Here we present an analysis of novel drug/target predictions, focusing on those that were not obvious based on known pharmacological crosstalk.
Advances in multi-parameter optimisation methods for de novo drug design
Summary This review article discusses recent developments in the methods and opinions around multi-parameter optimisation, focusing on applications to de novo drug…
Finding the rules for successful drug optimisation
Summary In this drug optimisation article, co-authored with Pfizer we discuss new ‘rule induction’ methods. These explore complex data to…
A structure-guided approach for protein pocket modeling and affinity prediction
We present a hybrid structure-guided strategy that combines molecular similarity, docking, and multiple-instance learning such that information from protein structures can be used to inform models of structure–activity relationships.
Addressing toxicity risk when designing and selecting compounds in early drug discovery
Summary In this article, ‘Addressing toxicity risk when designing and selecting compounds in early drug discovery‘, we discuss the application…
Protein function annotation by local binding site surface similarity
This paper demonstrates how the Surflex-PSIM method can help investigate hypotheses around protein function in cases where function cannot be determined by sequence similarity.
Preprint: considering the impact of ‘drug-like’ properties on the chance of success
Summary There are many different definitions of ‘drug-like’, with rules proposed based on property trends seen in successful drugs. In…
Iterative refinement of a binding pocket model: active computational steering of lead optimisation
Computational approaches for binding affinity prediction are most frequently demonstrated through cross-validation within a series of molecules or through performance shown on a blinded test set. Here, we show how such a system performs in an iterative, temporal lead optimization exercise. A series of gyrase inhibitors with known synthetic order formed the set of molecules that could be selected for “synthesis.”
Does your model weigh the same as a Duck?
This article discusses logic fallacies in the context of off-target predictive modelling.
Applying med chem transformations and multi-parameter optimisation
Summary This article on applying med chem transformations and multi-parameter optimisation describes the concepts and algorithms underlying StarDrop’s Nova module. We’ve developed…
Chemical Structural Novelty: On-Targets and Off-Targets
To compare chemical structures, we can look at a number of 2D and 3D characteristics. In this paper, a group of 358 drugs with overlapping pharmacology were assessed for chemical similarity, using a new framework.
Multi-parameter optimisation review article
In this multi-parameter optimisation review, we survey the range of methods used for MPO in drug discovery, compare their strengths…
Making priors a priority
Summary This article discusses a critical issue that the community needs to address address in order to use the predictive…
Overcoming psychological barriers to good discovery decisions
Summary This article explores the psychological barriers and risks of cognitive biases to R&D decision-making. It contrasts current practice with…