Refinement of Computational Access to Molecular Physicochemical Properties: From Ro5 to bRo5

Abstract

There is a need of computational tools to rank bRo5 drug candidates in the very early phases of drug discovery when chemical matter is unavailable. In this study, we selected three compounds: (a) a Ro5 drug (Pomalidomide), (b) a bRo5 orally available drug (Saquinavir), and (c) a polar PROTAC (CMP 98) to focus on computational access to physicochemical properties. To provide a benchmark, the three compounds were first experimentally characterized for their lipophilicity, polarity, IMHBs, and chameleonicity. To reproduce the experimental information content, we generated conformer ensembles with conformational sampling and molecular dynamics in both water and nonpolar solvents. Then we calculated Rgyr, 3D PSA, and IMHB number. An innovative pool of strategies for data analysis was then provided. Overall, we report a contribution to close the gap between experimental and computational methods for characterizing bRo5 physicochemical properties.

Conformational Sampling Deciphers the Chameleonic Properties of a VHL-Based Degrader

“…As recently shown for other bRo5 molecules [ 30 ], the simultaneous monitoring of multiple descriptors proved effective in obtaining information on the possible chameleon-like behaviour. Figure 2 shows results for PROTAC-1.…”

“…In contrast, the ensemble in water is composed of a mixture of highly folded (29%), semi-folded (56%), and linear (15%) conformations [ 19 ]. For all the NMR conformers, we calculated the three descriptors successfully used in previous publications [ 13 , 19 , 20 , 30 ] to characterize the chameleonic properties of bRo5 compounds: the solvent-accessible 3D polar surface area (3D PSA), the radius of gyration (R gyr ), and the number of intramolecular hydrogen bonds (nIMHB).…”

“…A few experimental and computational techniques have recently been employed to monitor chameleonic behaviour. For instance, chromatographic indexes such as ChamelogD [ 10 ] and the variation of the capacity factor in a nonpolar chromatographic system (PLRP-S) can be informative in this respect [ 30 , 31 ]. However, the experimental technique of choice is Nuclear Magnetic Resonance (NMR) spectroscopy, which can obtain the atomic resolution and dynamic details of a molecule in solution [ 32 , 33 , 34 , 35 ] and monitor variation in physicochemical properties [ 20 ].…”

“…However, the experimental technique of choice is Nuclear Magnetic Resonance (NMR) spectroscopy, which can obtain the atomic resolution and dynamic details of a molecule in solution [ 32 , 33 , 34 , 35 ] and monitor variation in physicochemical properties [ 20 ]. Concerning computational predictions, recent results indicate that using different tools to generate conformational ensembles provides different sets of conformers [ 30 ]. Thus, there is a strong need to benchmark in silico predictions with experimental data.…”

“…Describing polarity via 3D PSA is a valid strategy to explain important properties such as permeability and solubility [ 38 , 39 , 40 , 41 ]. Notably, the 3D PSA method employed here is directly comparable with topological PSA (TPSA) values [ 30 ]. R gyr is a descriptor mainly related to the shape of a conformer proving useful to model the cell permeability of flexible molecules [ 9 , 20 ], and nIMHB is a widely known driver of chameleonicity [ 24 , 26 ].…”