A guide to drug discovery: Hit and lead generation: beyond high-throughput screening

  title={A guide to drug discovery: Hit and lead generation: beyond high-throughput screening},
  author={Konrad H. Bleicher and Hans-Joachim B{\"o}hm and Klaus M{\"u}ller and Alexander I Alanine},
  journal={Nature Reviews Drug Discovery},
The identification of small-molecule modulators of protein function, and the process of transforming these into high-content lead series, are key activities in modern drug discovery. The decisions taken during this process have far-reaching consequences for success later in lead optimization and even more crucially in clinical development. Recently, there has been an increased focus on these activities due to escalating downstream costs resulting from high clinical failure rates. In addition… 
Lead Optimization in Drug Discovery
“closed-loop” work flows are in place such that synthesis and primary screening operate on a 1-week turnaround for up to 48 compounds/week with DMPK data cycling every other week to guide compound design, which provides expedited timelines for the development of proof-of-concept compounds and clinical candidates with limited human resources.
Advances in Lead Generation.
High-Throughput Synthesis of Diverse Compound Collections for Lead Discovery and Optimization.
The crucial factors of library design strategies from the perspective of synthetic chemistry are discussed, giving a brief historic background and a summary of current approaches.
Integration of virtual and high throughput screening in lead discovery settings.
There are numerous applications underlining its relevance that early-stage pharmaceutical drug research could benefit from a combined approach to high throughput and virtual screening.
High Throughput Screening
HTS is at the core of the drug discovery process, and so it is critical to design and implement HTS assays in a comprehensive fashion involving scientists from the disciplines of biology, chemistry,


Lead generation--enhancing the success of drug discovery by investing in the hit to lead process.
The processes and tools employed in the hit to lead process in such a "Lead Generation" group will be surveyed, emphasising the possible gains in productivity through close, early interactions between chemistry and other expert groups.
Integration of virtual and high-throughput screening
There are several success stories and good indications that early-stage drug discovery will benefit greatly from a more unified and knowledge-based approach to biological screening, despite the many technical advances towards even higher throughput that are made in the screening arena.
PRO_SELECT: combining structure-based drug design and array-based chemistry for rapid lead discovery. 2. The development of a series of highly potent and selective factor Xa inhibitors.
Pro_SELECT, a tool for the virtual screening of libraries for fit to a protein active site, has been used to find novel leads against the serine protease factor Xa.
Drug discovery: a historical perspective.
The biotech industry is establishing itself as the discovery arm of the pharmaceutical industry, and in bridging the gap between academia and large pharmaceutical companies, the biotech firms have been effective instruments of technology transfer.
Chemical ligands, genomics and drug discovery.
Chemogenomics: bridging a drug discovery gap.
An overview of the disciplines involved in "chemogenomics" is given and the possible implications of this novel paradigm in drug discovery for the near future are discussed.
Prediction of 'drug-likeness'.
In silico identification of novel therapeutic targets.
Structure-based screening and design in drug discovery.
The druggable genome
An assessment of the number of molecular targets that represent an opportunity for therapeutic intervention is crucial to the development of post-genomic research strategies within the pharmaceutical