Abstract
Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by the three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted by the development of synchrotron radiation sources. Structures of known drugs or inhibitors were used to guide the development of leads. The growth of high-throughput screening during the late 1980s and the early 1990s in the pharmaceutical industry of chemical libraries of hundreds of thousands of compounds of molecular weight of approximately 500 Da was impressive but still explored only a tiny fraction of the chemical space of the predicted 1040 drug-like compounds. The use of fragments with molecular weights less than 300 Da in drug discovery not only decreased the chemical space needing exploration but also increased promiscuity in binding targets. Here we discuss advances in X-ray fragment screening and the challenge of identifying sites where fragments not only bind but can be chemically elaborated while retaining their positions and binding modes. We first describe the analysis of fragment binding using conventional X-ray difference Fourier techniques, with Mycobacterium abscessus SAICAR synthetase (PurC) as an example. We observe that all fragments occupy positions predicted by computational hotspot mapping. We compare this with fragment screening at Diamond Synchrotron Light Source XChem facility using PanDDA software, which identifies many more fragment hits, only some of which bind to the predicted hotspots. Many low occupancy sites identified may not support elaboration to give adequate ligand affinity, although they will likely be useful in drug discovery as ‘warm spots’ for guiding elaboration of fragments bound at hotspots. We discuss implications of these observations for fragment screening at the synchrotron sources.This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’.
Highlights
Structure-guided drug discovery has its origins in both academia and the pharmaceutical industry in the 1970s
An alternative approach to the challenge was found in decreasing the size of the molecules from the molecular weight of approximately 500 Da to less than 300 Da, which decreased the size of chemical space needing exploration but at the same time increased their promiscuity in binding targets
This was less of a challenge, with the focus often being on early discovery rather than securing intellectual property (IP) and in the study of neglected diseases, where the financial returns are unlikely to be great given their prevalence in developing countries or small patient populations
Summary
Structure-guided drug discovery has its origins in both academia and the pharmaceutical industry in the 1970s (for reviews, see [1,2]). An alternative approach to the challenge was found in decreasing the size of the molecules from the molecular weight of approximately 500 Da to less than 300 Da, which decreased the size of chemical space needing exploration but at the same time increased their promiscuity in binding targets This laid down the basic principles of fragment-based drug discovery (FBDD) [see [2], for review]. The pharmaceutical industry was initially sometimes hesitant to exploit the facilities, because they concerned crystals involving compounds with large intellectual property (IP) value to be sent outside the company In academia, this was less of a challenge, with the focus often being on early discovery rather than securing IP and in the study of neglected diseases, where the financial returns are unlikely to be great given their prevalence in developing countries or small patient populations. We do not discuss the stages of fragment-linking or chemical elaboration, which are being pursued in parallel for PurC as a target for combatting infections by M. abscessus in cystic fibrosis
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