Prediction of Chameleonic Efficiency

Abstract

Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Å 2 was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R 2 = 0.92) with an experimental measure of hydrogen bond donor potential, Δlog P oct-tol , was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.

Trends in Molecular Properties, Bioavailability, and Permeability across the Bayer Compound Collection

“…Indeed, it has been shown previously that the cross-sectional area threshold of 80 Å 2 is critical to tip the balance toward passive diffusion being high enough to effectively shorten the membrane residence time of drug molecules, below which efflux pumps can readily pick up the molecules from the membrane. ,, This property has recently been termed “molecular chameleonicity” and can afford higher than expected permeability for PROTACs and other bRo5 compounds . Drug design teams seeking to incorporate chameleonic properties may benefit by studying the behavior of their compounds in both aqueous and non-polar solvent environments; the parameter of “chameleonic efficiency” has been proposed for this purpose . Another useful tool in the analysis of permeability for bRo5 molecules is the experimental polar surface area (EPSA) method, a chromatographic technique developed by Pfizer for the analysis of intramolecular hydrogen bonding .…”

“…43 Drug design teams seeking to incorporate chameleonic properties may benefit by studying the behavior of their compounds in both aqueous and non-polar solvent environments; the parameter of "chameleonic efficiency" has been proposed for this purpose. 44 Another useful tool in the analysis of permeability for bRo5 molecules is the experimental polar surface area (EPSA) method, a chromatographic technique developed by Pfizer for the analysis of intramolecular hydrogen bonding. 45 The EPSA technique has been successfully applied for the optimization of compounds with permeability challenges, including peptides 46 and other large, polar molecules.…”

PROTAC degraders as chemical probes for studying target biology and target validation

“…34 In this context, design of PROTAC molecules with a “chameleonic behavior”, thus the capacity of a molecule to hide polarity in non-polar environments and expose it in water, is an interesting strategy which can take advantage of predictive computational methods, such as molecular dynamics. 35 Additional strategies for the design of PROTACs with improved cell membrane penetration employ shielding of polar groups by bulky non-polar moieties 36 or replacement of an amide functionality for an ester. 37 Recently, a method combining parallel artificial membrane permeability assay (PAMPA) and lipophilic permeability efficiency (LPE) has been developed in order to better understand how structural elements of VHL based PROTACs influence compound permeability.…”

Prediction of Toluene/Water Partition Coefficient in the SAMPL9 Blind Challenge: Assessment of Machine Learning and IEF-PCM/MST Continuum Solvation Models

“…Furthermore, the experimental alkane/water and toluene/water partition systems have given insights into the 'chameleonic' properties of drugs whose chemical space is beyond of the metrics of the rule-of-five, although experimental limitations that fall on the low solubility of compounds in alkane-type solvents may limit their application [26][27][28]. As an example, it has been shown that macrocyclic drugs populate significantly less polar and more compact conformational ensembles in an apolar than in a polar environment, which enables to balance aqueous solubility and cell permeability [22].…”