Improving the hit-to-lead process: data-driven assessment of drug-like and lead-like screening hits

doi:10.1016/S1359-6446(05)03700-1

Drug Discovery Today

Volume 11, Issues 3–4, February 2006, Pages 175-180

https://doi.org/10.1016/S1359-6446(05)03700-1 Get rights and content

Drug-like and lead-like hits derived from HTS campaigns provide good starting points for lead optimization. However, too strong emphasis on potency as hit-selection parameter might hamper the success of such projects. A detailed absorption, distribution, metabolism, excretion and toxicology (ADME–Tox) profiling is needed to help identify hits with a minimum number of (known) liabilities. This is particularly true for drug-like hits. Herein, we describe how to break down large numbers of screening hits and we provide a comprehensive overview of the strengths and weaknesses for each structural class. The overall profile (e.g. ligand efficiency, selectivity and ADME–Tox) is the distinctive feature that will define the priority for follow-up.

Section snippets

Hits, leads and drugs

Hits are defined as nonreactive compounds [3] of verified structure and purity, with a confirmed minimal in vitro potency (<20 μM) derived from HTS. By contrast, leads are compounds that, in addition to their potency, show some degree of selectivity for the given target, along with confirmed specific binding, emerging SAR, biophysical and absorption, distribution, metabolism, excretion and toxicity (ADME–Tox) properties, which are promising for their eventual optimization into small-molecule

Potency alone is a false predictor for hit selection

It is now widely accepted that proper selection of screening hits is of central importance for the success of lead optimization efforts [9] and that these hits will ideally exhibit lead-like properties (i.e. possess a well-balanced mixture of potency, selectivity and other important features). Such features would include favorable physicochemical properties, absence of toxophores and amenability to the rapid synthesis of chemical analogues [10]. More recently, the concept of ligand efficiency

The importance of drug-like hits

Collection of ADME–Tox data will be tedious for the screening of hit lists comprising a few thousand compounds. Therefore, it might be tempting to reduce this number by simply applying filters based on the definition of lead-likeness. A successful example of the metamorphosis of a lead-like hit into a candidate for clinical development is the kinase inhibitor sorafenib (1), currently in Phase III clinical development (Figure 1) [15]. This compound was derived from the commercially available

Implementation of a data-driven hit-to-lead process

The term hit-to-lead describes the process of filtering and assessing hits (derived from HTS) and the limited chemical modifications of these hits to establish an initial SAR. Data other than potency and selectivity of a given hit or cluster of hits are collected to allow for a data-driven decision on which class should be advanced into the lead optimization phase [17]. The goal is to identify compounds with a minimum number of known liabilities that will provide the optimal starting point for

Discussion

Processing through the described cascade will generate a data package for each selected cluster and singleton. These data, in combination with each compound's biological profile, need to be assessed by experienced medicinal chemists supported by efficient tools for data analysis and visualization [18, 19]. The prioritization of the hits for chemical follow-up is clearly not a deterministic process. Typically, from a successful screen 3–5 structural classes remain worthwhile for initiating the

Acknowledgements

We would like to thank all our colleagues from the hit-to-lead groups and our screening departments with whom we had many hours of fruitful discussions about specific aspects of the hit-to-lead process. Their input certainly has helped to shape the described cascade and to test it under ‘real life’ conditions. We would also like to thank all our colleagues who have contributed with their experience to set up the traffic light systems. Finally, we would like to thank J. R. Proudfoot for

References (21)

J. Drews
Strategic trends in the drug industry
Drug Discov. Today
(2003)
RishtonG.M.
Nonleadlikeness and leadlikeness in biochemical screening
Drug Discov. Today
(2003)
LipinskiC.A.
Experimental and computational approaches to estimate solubility and permeability in drug discovery settings
Adv. Drug Del. Rev.
(1997)
ProudfootJ.R.
Drugs, leads, and drug-likeness: an analysis of some recently launched drugs
Bioorg. Med. Chem. Lett.
(2002)
G.M. Milne
Pharmaceutical productivity - the imperative for new paradigms
Annu. Rep. Med. Chem.
(2003)
P. Gribbon et al.
High-throughput drug discovery: what can we expect from HTS?
Drug Discov. Today
(2005)
HopkinsA.L.
Ligand efficiency: a useful metric for lead selection
Drug Discov. Today
(2004)
D.C. Rees
Fragment-based lead discovery
Nat. Rev. Drug Discov.
(2004)
S.J. Teague
The design of leadlike combinatorial libraries
Angew. Chem. Int. Ed. Engl.
(1999)
LajinessM.S.
Molecular properties that influence oral drug-like behavior
Curr. Opin. Drug Discov. Devel.
(2004)

There are more references available in the full text version of this article.

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ReviewImproving the hit-to-lead process: data-driven assessment of drug-like and lead-like screening hits

Section snippets

Hits, leads and drugs

Potency alone is a false predictor for hit selection

The importance of drug-like hits

Implementation of a data-driven hit-to-lead process

Discussion

Acknowledgements

Drug Discov. Today

Drug Discov. Today

Adv. Drug Del. Rev.

Bioorg. Med. Chem. Lett.

Annu. Rep. Med. Chem.

Drug Discov. Today

Drug Discov. Today

Fragment-based lead discovery

Nat. Rev. Drug Discov.

The design of leadlike combinatorial libraries

Angew. Chem. Int. Ed. Engl.

Molecular properties that influence oral drug-like behavior

Curr. Opin. Drug Discov. Devel.

Review
Improving the hit-to-lead process: data-driven assessment of drug-like and lead-like screening hits