Abstract
The ligand efficiency (LE) indexes have long been used as decision-making criteria in drug discovery and development. However, in the context of fragment-based drug design (FBDD), these metrics often exhibit a strong emphasis toward the selection of highly efficient “core” fragments for potential optimization, which are not usually considered as parts of a larger molecule with a size typical for a drug. In this study, we present a relative group contribution (RGC) model intended to predict the efficiency of a drug-sized compound in terms of its component fragments. This model could be useful not only in rapidly predicting all the possible combinations of promising fragments from an earlier hit discovery stage, but also in enabling a relatively low-LE fragment to become part of a drug-sized compound as long as it is “rescued” by other high-LE fragments.
Highlights
Ligand efficiency metrics have been applied as a decision-making strategy nearly universally accepted during the last two decades (Hopkins et al, 2014)
We propose that a relative group contribution (RGC) model based on the efficiency of its component fragments may estimate the efficiency of a drug-sized compound
The present study pretends to propose the RGC model as an innovative and effective approach to apply in drug design
Summary
Ligand efficiency metrics have been applied as a decision-making strategy nearly universally accepted during the last two decades (Hopkins et al, 2014). Several independent studies in the past two decades have indicated an overemphasis on potency by the pharmaceutical industry (Albert et al, 2007; Hopkins et al, 2014) Still, other factors such as chemical novelty (Medina-Franco et al, 2014), selectivity fine-tuning (Costantino and Barlocco, 2018), structural alerts avoidance (Jasial et al, 2017), and synthetic accessibility (Fukunishi et al, 2014) are increasingly playing a key role in drug design. We propose that a relative group contribution (RGC) model based on the efficiency of its component fragments may estimate the efficiency of a drug-sized compound This model calculates the minimum efficiency required for unknown fragments by considering the efficiency of those already known, which facilitates a rapid elucidation of the best combinations of fragments. The efficiency of each fragment (regarded as the entire ratio and not just the quotient) is, in principle, dependent on each other, excepting in cases of two fragments when the N for them is equal to each other (and their weight is equivalent), or in cases when three or more fragments are involved
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