Improving the Plausibility of Success with Inefficient Metrics

Michael D. Shultz*

Novartis Institutes for Biomedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States

ACS Med. Chem. Lett., 2014, 5 (1), pp 2–5

DOI: 10.1021/ml4004638

Publication Date (Web): November 21, 2013

*E-mail: michael.shultz@novartis.com. Phone: +1 617-871-7551.

Abstract

To increase the probability of success in drug discovery, the concept of drug-like properties was introduced. Efficiency metrics that normalize potency against these properties could help reach drug-like space more efficiently. Potential reasons for the inefficient use of metrics and suboptimal decision making are discussed.

Keywords:

decision making; drug-likeness; efficiency metrics; fragment-based drug design; Ligand efficiency (LE); lipophilic efficiency (LipE);

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Improving the Plausibility of Success with Inefficient Metrics

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Viewpoint

Improving the Plausibility of Success with Inefficient Metrics

Abstract

Keywords:

Proofs

Benchmarking the Predictive Power of Ligand Efficiency Indices in QSAR

Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space

Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy

Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study

Accurate Binding Free Energy Predictions in Fragment Optimization

Validity of Ligand Efficiency Metrics

Computer-aided drug discovery research at a global contract research organization

Kinetics, Thermodynamics, and Ligand Efficiency Metrics in Drug Discovery

The ways and means of fragment-based drug design

Molecular inflation, attrition and the rule of five

Fragment-Based Lead Generation

Lead Quality

Compound high-quality criteria: a new vision to guide the development of drugs, current situation

Fragment Screening in Complex Systems

Ligand Efficiency Metrics and their Use in Fragment Optimizations

The Evolving Role of the Medicinal Chemist

Protein–Ligand Docking: Virtual Screening and Applications to Drug Discovery

Ligand efficiency metrics: why all the fuss?

The impact of binding thermodynamics on medicinal chemistry optimizations

In silico tools used for compound selection during target-based drug discovery and development

Lead optimization attrition analysis (LOAA): a novel and general methodology for medicinal chemistry

Combining Organometallic Reagents, the Sulfur Dioxide Surrogate DABSO, and Amines: A One-Pot Preparation of Sulfonamides, Amenable to Array Synthesis

Combining Organometallic Reagents, the Sulfur Dioxide Surrogate DABSO, and Amines: A One-Pot Preparation of Sulfonamides, Amenable to Array Synthesis

Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs

Advances in multiparameter optimization methods for de novo drug design

Ligand efficiency metrics considered harmful

Alternative variables in drug discovery: promises and challenges

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