The identification of suitable chemical starting points is a cornerstone of modern small molecule drug discovery. During the past decade fragment screening has become a widely adopted technique. A key strength is that it provides hit compounds, which (although often exhibiting weak target affinity) can provide comparatively high ligand efficiency and usually very attractive physicochemical properties. However, a weakness is the requirement for structural information on target-ligand binding for efficient structure-based optimisation to increase potency.
In this issue of Drug Discovery Today, Editor’s Choice, I highlight four recent papers that consider how to make the best use of fragments both in terms of their optimisation and their application more broadly in drug discovery. The papers featured are all available as free downloads, so please have a look at them; I’m sure that you will find them interesting and thought provoking.
For the medicinal chemist seeking to optimise a fragment starting point for the first time the plethora of binding efficiency metrics that have been reported in the literature can be both daunting and confusing. Sabine Schultes, Chris de Graaf, Eric Haaksma, Iwan de Esch, Rob Leurs, Oliver Krämer provide great insight into the more commonly used efficiency metrics (ligand efficiency, group efficiency, fit quality and ligand lipophilicity efficiency) and nicely illustrate with worked examples how they can be applied in concert to give complementary insights during fragment optimization.
In our review on ‘Fragments – past, present and future’ my colleagues, Rich Law, Osamu Ichihara, Thomas Hesterkamp, Dave Hallett, and I propose the ab initio fragment molecular orbital (FMO) method as being a powerful technique to employ for analysis of fragment co-crystal structures to aid the structure-based fragment optimisation. We also discuss in the case of histamine receptors how fragment methods may be utilised in combination with detailed GPCR modelling to aid the fragment optimisation process.
Fredrik Edfeldt, Rutger Folmer and Alex Breeze from AstraZeneca recommend using an initial fragment screen to determine the ligandability of new targets. An insightful analysis of the ligandability score, the success of HTS and entry into hit-to-lead is presented for 36 targets. It is concluded that ligandability screening is highly predictive for project success and is thus a powerful tool for reducing attrition in drug discovery by filtering out non-ligandable targets at the pre-project stage.
Finally, Giovanni Bottegoni, Angelo Favia, Maurizio Recanatini and Andre Cavalli consider the potential of fragment methods for the derivation of drugs that exhibit polypharmacology. They suggest a workflow strategy for fragment-based multitarget discovery that involves fragment screening, and also potentially the multiple solvent crystal structure (MSCS) method, allied to computational techniques to generate hybrid, fused or chimeric multitarget compounds.
I hope that you enjoy reading the articles offered in this newsletter and I hope that you will agree that they illustrate that the potential for greater application of fragment methods in drug discovery continues to grow.
Biography
Mark Whittaker was born in Cambridge, England in 1958 and studied at the University of York (1976–1982), obtaining a BA (Hons) in Chemistry and a DPhil in the field of mechanistic organic chemistry. Subsequently he took post-doctoral positions firstly at York University, Toronto, with Professor Cliff Leznoff and Professor Colin McArthur on polymer supported organic synthesis (1982–1985) and secondly at the University of Oxford with Professor Steve Davies on the use of organometallic reagents in asymmetric synthesis (1985–1987). In 1987, he joined British Biotechnology and held a number of positions in Medicinal Chemistry and was latterly Director of Chemistry. Mark joined Evotec in 2001 where he is Senior Vice President Drug Discovery. He has contributed to the discovery of 12 drug candidates that have progressed into human clinical trials, is an inventor on over 50 patent applications and author of over 100 literature publications.