The influence of drug-like concepts on decision-making in medicinal chemistry

@article{Leeson2007TheIO,
  title={The influence of drug-like concepts on decision-making in medicinal chemistry},
  author={Paul D. Leeson and Brian Springthorpe},
  journal={Nature Reviews Drug Discovery},
  year={2007},
  volume={6},
  pages={881-890}
}
The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences… 
The significance of acid/base properties in drug discovery.
TLDR
Considering pK(a) values in conjunction with other molecular properties is of great significance and has the potential to be used to further improve the efficiency of drug discovery.
The influence of lead discovery strategies on the properties of drug candidates
TLDR
Analysis of the physicochemical properties of a large database of hits and corresponding leads identified in the past decade shows that this undesirable phenomenon can be traced back to the nature of high-throughput screening hits and hit-to-lead optimization practices.
Finding the sweet spot: the role of nature and nurture in medicinal chemistry
TLDR
Scientific, strategic, organizational and cultural considerations for medicinal chemistry practices are discussed, with the aim of promoting more effective use of what is already known, as well as a wider appreciation of the risks of pursuing suboptimal compounds.
Recent Advances in Physicochemical and ADMET Profiling in Drug Discovery
TLDR
Recent advances in accurate assessment of solubility and other physicochemical parameters are reviewed and the impact of these tools on assisting drug‐discovery teams in establishing in vitro–in vivo correlation (IVIVC) as well as structure–property relationship (SPR) will be presented.
Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidates
TLDR
The concept of drug efficiency is introduced as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate.
The impact of physicochemical and molecular properties in drug design: navigation in the "drug-like" chemical space.
TLDR
The case of PPARs, a nuclear receptor family, is discussed in detail in regard to the chemical space covered by the ligands, focusing on the high demands of the ligand binding domain in both lipophilicity and molecular size.
Medicinal chemistry: Exploring the third dimension
TLDR
Overall, this study identifies Fsp3 as a surrogate for molecular complexity that could be used to improve the success of drug development programmes, and highlights a key limitation of synthesizing chemical libraries for screening by using reactions that link flat aromatic moieties.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 63 REFERENCES
Drug-like properties: guiding principles for design - or chemical prejudice?
TLDR
Novel library synthesis, creating new chemical classes to address intellectual property, toxicity issues, and less chemically tractable targets, though considered risky, is warranted.
A guide to drug discovery: The role of the medicinal chemist in drug discovery — then and now
TLDR
Historical perspective could provide insights in to how to improve the current model for drug discovery by helping the medicinal chemist regain the creative role that contributed to past successes.
Lead- and drug-like compounds: the rule-of-five revolution.
  • C. Lipinski
  • Biology, Medicine
    Drug discovery today. Technologies
  • 2004
A comparison of physiochemical property profiles of development and marketed oral drugs.
TLDR
A study in which the distributions of physiochemical properties of oral drugs in different phases of clinical development are compared to those already marketed, showing that the mean molecular weight of orally administered drugs in development decreases on passing through each of the different clinical phases and gradually converges toward the mean Molecular weight of marketed oral drugs.
Organic Chemistry in Drug Discovery
The role played by organic chemistry in the pharmaceutical industry continues to be one of the main drivers in the drug discovery process. However, the precise nature of that role is undergoing a
Analysis of Pharmacology Data and the Prediction of Adverse Drug Reactions and Off‐Target Effects from Chemical Structure
TLDR
This is the first attempt to predict adverse drug reactions across hundreds of categories from chemical structure alone and features of the models are interpretable and back‐projectable to chemical structure, raising the possibility of rationally engineering out adverse effects.
Identification and evaluation of molecular properties related to preclinical optimization and clinical fate.
  • J. Blake
  • Computer Science, Medicine
    Medicinal chemistry (Shariqah (United Arab Emirates))
  • 2005
TLDR
This perspective will cover recent efforts that have had the greatest influence on defining the optimal range of physical properties of compounds that are intended to act as human therapeutic agents and examine the optimal physicochemical properties for oral absorption based on solubility, permeability, and a few easily computed parameters.
Analysis of drug-induced effect patterns to link structure and side effects of medicines
TLDR
The translation of adverse effect data derived from 1,045 prescription drug labels into effect spectra is described and their utility for diagnosing drug-induced effects of medicines is shown and it is shown that biospectrum analysis, in concert with effect spectrum analysis, provides an alignment between preclinical and clinical drug- induced effects.
Characteristic physical properties and structural fragments of marketed oral drugs.
TLDR
Oral drugs tend to be lighter and have fewer H-bond donors, acceptors, and rotatable bonds than drugs with other routes of administration, and it is demonstrated that the mean property values for oral drugs do not vary substantially with respect to launch date, suggesting that the range of acceptable oral properties is independent of synthetic complexity or targeted receptor.
Predicting ADME properties and side effects: the BioPrint approach.
TLDR
The importance of training set size and diversity in model development, the implementation of linear and neighborhood modeling approaches, and the use of in silico methods to predict potential clinical liabilities are discussed.
...
1
2
3
4
5
...