In Vitro Measurement of Drug Efficiency Index to Aid Early Lead Optimization

Valkó, Klára; Chiarparin, Elisabetta; Nunhuck, Shenaz; Montanari, Dino

doi:10.1002/jps.23305

Cited by 34 publications

(36 citation statements)

References 22 publications

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“…Thus, when we plot the potency (pIC50) values in the function of the Drug Efficiency Index (DEI), which is the sum of the pIC50 and the log DE, the marketed drugs are around the line of unity (see Figure 7). It has been observed [51] that discovery compounds usually have very narrow potency range (pIC50 between 7 to 9), but a much broader range of drug efficiency index. Based on the retrospective analysis it turned out that compounds that are on the right side of the line of unity survived the strict candidate selection procedure and showed a good PK/PD profile [51].…”

Section: Resultsmentioning

confidence: 99%

“…The same technology has been applied to estimate the Maximum Drug Efficiency (HPLC DEmax) value, that represents the maximum drug efficiency that can be achieved when the bioavailability is 100 %, and there is no permeability barrier or active transport to disturb the steady state equilibrium. This can be expressed as the reciprocal value of the steady-state unbound volume of distribution [51].…”

Section: Methodsmentioning

confidence: 99%

“…The HPLC DE max data were calculated using the reciprocal value of the MB/PB log V du data and validated against human clinical DE max data [51]. Table 5.…”

Section: Methodsmentioning

confidence: 99%

“…Estimating the potential clinical dose as early as possible is an important aspect of the drug discovery process to help select the optimal compound profile and highest probability of successful progression to the clinic [49][50]. Valko et al [51] highlighted that the maximum achievable drug efficiency (DE max ) that can be obtained assuming (i) 100 % bioavailability, (ii) no permeability barrier and (iii) no active transport could be calculated using in vitro biomimetic measurements, essentially the Regis IAM MB/PB Technology® that we are proposing in this paper as a useful tool in early drug discovery [51]. The drug efficiency concept as a design parameter has the advantage that it can be estimated from in vitro measurements, and can be monitored during the drug development process to see how the early estimation performs when in vivo measurements become available pre-clinically, or from human clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

Valkó¹,

Teague²,

Pidgeon³

2017

ADMET DMPK

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The HPLC DE max data were calculated using the reciprocal value of the MB/PB log V du data and validated against human clinical DE max data [51]. Table 5.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

Valkó¹,

Teague²,

Pidgeon³

2017

ADMET DMPK

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“…Finally, LLE correlates positively with the drug efficiency index (DEI). 80 DEI is a very useful metric for application in lead optimisation projects, since it combines the estimated fraction of the dose that is available free in plasma with in vitro potency.…”

Section: Application Of Efficiency Metrics In Optimisationmentioning

confidence: 99%

The role of ligand efficiency metrics in drug discovery

Hopkins

Keserü

Leeson

et al. 2014

Nat Rev Drug Discov

938

928

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Summary Ligand efficiency measures quantify the molecular properties, particularly size and lipophilicity, of small molecules that are required to gain binding affinity to a drug target. For example, ligand efficiency, is the binding free energy per heavy atom count (LE = G/HA) and lipophilic ligand efficiency (LLE = pIC 50 or KicLogP/D). There are additional efficiency measures for groups in a molecule, and for combinations of size and lipophilicity. The application of ligand efficiency metrics has been widely reported in the selection and optimisation of fragments, hits, and leads. In particular, optimisation of lipophilic ligand efficiency shows that it is possible to increase affinity and reduce lipophilicity at the same time, even with challenging 'lipophile-preferring' targets. Mean ligand efficiency measures of molecules acting at a specific target, when combined with their drug-like physical properties, is a practical means of estimating target 'druggability.' This is exemplified with 480 targetassay pairs from the primary literature. Across these targets correlations between biological activity in vitro and physical properties are generally weak, showing that increasing activity by increasing physical properties is not always necessary. Charles H. ReynoldsCharles Reynolds is currently President of Gfree Bio, a modeling and structure-based design company in AbstractThe judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates.

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