Quantitative Estimate Index for Early-Stage Screening of Compounds Targeting Protein-Protein Interactions.

Takatsugu Kosugi,Masahito Ohue

doi:10.3390/ijms222010925

Takatsugu Kosugi, Masahito Ohue

Open Access

https://doi.org/10.3390/ijms222010925

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Abstract

Drug-likeness quantification is useful for screening drug candidates. Quantitative estimates of drug-likeness (QED) are commonly used to assess quantitative drug efficacy but are not suitable for screening compounds targeting protein-protein interactions (PPIs), which have recently gained attention. Therefore, we developed a quantitative estimate index for compounds targeting PPIs (QEPPI), specifically for early-stage screening of PPI-targeting compounds. QEPPI is an extension of the QED method for PPI-targeting drugs that models physicochemical properties based on the information available for drugs/compounds, specifically those reported to act on PPIs. FDA-approved drugs and compounds in iPPI-DB, which comprise PPI inhibitors and stabilizers, were evaluated using QEPPI. The results showed that QEPPI is more suitable than QED for early screening of PPI-targeting compounds. QEPPI was also considered an extended concept of the “Rule-of-Four” (RO4), a PPI inhibitor index. We evaluated the discriminatory performance of QEPPI and RO4 for datasets of PPI-target compounds and FDA-approved drugs using F-score and other indices. The F-scores of RO4 and QEPPI were 0.451 and 0.501, respectively. QEPPI showed better performance and enabled quantification of drug-likeness for early-stage PPI drug discovery. Hence, it can be used as an initial filter to efficiently screen PPI-targeting compounds.

Highlights

Protein-protein interactions (PPIs) have attracted attention as drug targets since the early 2000s [1,2,3,4,5]
We developed a method named quantitative estimate index for compounds targeting PPIs (QEPPI) (Quantitative Estimate Index for Compounds Targeting Protein-Protein Interactions), which is useful for early-stage PPI-targeting drug discovery based on data from compounds that have undergone extensive PPI inhibition or stabilization experiments, rather than on data from marketed PPItargeting drugs
QEPPI is an index in the early-stages of PPI drug discovery, and the prerequisites for using the dataset to model QEPPI are as follows:

Summary

Introduction

Protein-protein interactions (PPIs) have attracted attention as drug targets since the early 2000s [1,2,3,4,5]. An index that can be used to computationally select compounds that are likely to target PPIs is needed. The QED index models these properties using data available from 771 orally administered drugs already approved by the U.S Food and Drug Administration (FDA). This index is not an appropriate measure for PPItargeting compounds, which require a relatively large surface area of the protein with which to interact. New measures should be developed for PPI-targeting drugs [15]

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Discussion

Conclusion