Medicinal chemists need guidance on how to improve bioavailability (%F) for their compound series. They must consider over a dozen compound properties to adjust: solubility, logP, logD, Peff, CLint, PPB, RBP, MW, efflux, PSA, flexibility,pKa1, pKa2, pKb1, etc. Since the difficulty of multi-parameter optimization grows exponentially with the number of variables, efficient %F optimization requires identifying the few most influential properties for their specific medchem series. These properties are also the principal inputs to physiologically-based pharmacokinetics (PBPK) models, which simulate the journey of a drug through an animal. Usually, PBPK simulations are carefully tuned for a few advanced drug candidates, using a combination of in vitro, in vivo and calculated inputs, to estimate human doses for clinical trials, or to prioritize compounds for expensive animal studies.Here, GastroPlus PBPK models are instead customized for entire medchem series based on 15 to 20 rat PK studies. A key innovation was building a local QSAR for effective intrinsic clearance. All inputs are subsequently computed from structure alone, so the models can be applied to virtual molecules in advance of synthesis. Beyond that, performing 1000s of PBPK calculations over the active property ranges for the series characterizes its “bioavailability landscape”. Analyzing the landscape with PLS-based global sensitivity analysis (GSA) identifies the most influential properties affecting %F. Innovations here included discovering that only the pKas straddling the isoelectric point influence %F, and employing the large ZINC database of drug-like compounds to eliminate chemically incompatible property combinations. The resulting analysis identifies the important few properties to adjust for the series as a whole, as well as more specific advice for optimizing %F around particular compounds of interest. The PLS equation is also used in multi-parameter scoring functions for structure-based design of potent, bioavailable compounds. Our ultimate ambition with these multiscale molecular/whole-animal simulations is SBDD of animal efficacy.

Rational bioavailability design: Optimizing bioavailability in lead op with Global Sensitivity Analysis of Physiologically-Based PK (GSA of PBPK)

253rd National Meeting (2017)

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