Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Sep 22;65(18):12068-12083.
doi: 10.1021/acs.jmedchem.2c00774. Epub 2022 Sep 12.

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

Matteo Rossi Sebastiano  1 , Diego Garcia Jimenez  1 , Maura Vallaro  1 , Giulia Caron  1 , Giuseppe Ermondi  1
Affiliations

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

Matteo Rossi Sebastiano et al. J Med Chem. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following competing financial interest(s): The UniTO laboratory receives sponsored support for PROTAC related research from Chiesi Farmaceutici and Kymera Therapeutics. Moreover, a commercial contract on PROTACs has been recently signed with Boehringer Ingelheim.

Figures

Figure 1
Figure 1
Structure of the three molecules selected: (A) Pomalidomide, (B) Saquinavir, and (C) CMP 98.
Figure 2
Figure 2
Pomalidomide (yellow), CMP 98 (green), and Saquinavir (violet) behavior in the PLRP-S system. The gray dashed line at 95% CH3CN highlights the slope change.
Figure 3
Figure 3
Correlation of molecular volume to Rgyr for (A) Pomalidomide, red, (B) Saquinavir, green, and (C) CMP 98, blue. (D) Conformational ensembles of the three molecules plotted together. Rgyr (Å) vs van der Waals volume (Å3). R is presented as Bravais–Pearson coefficient.
Figure 4
Figure 4
IMHB detection in CMP 98 and Saquinavir for conformational sampling in water/chloroform (CSw/CSc) molecular dynamics in water/toluene (MDw/MDt) and SMD tunneling in water/toluene (SMDw/SMDt). ΔMean is the difference of the average of IMHBs in nonpolar solvent and water. Median values are presented as black dashed lines.
Figure 5
Figure 5
Conformational Sampling: 2D plot of 3D PSA vs Rgyr in water and chloroform: (A) Saquinavir and (B) CMP 98.
Figure 6
Figure 6
SMD Tunneling: density plots of Saquinavir in water (A) and toluene (B) and CMP 98 in water (C) and toluene (D) highlighting the dispersion patterns of the generated conformers in the 2D plot of 3D PSA vs Rgyr. The color scale is expressed as conformer frequency per tile. Blue perimeter stands for water, orange for toluene, and orange/blue crosses highlight the solvent-based shift of the inner cluster.
Figure 7
Figure 7
Conformational Sampling: distribution of IMHB regions based on size and polarity. (A,B) Saquinavir in water (A) and chloroform (B). (C,D) CMP 98 in water (C) and chloroform (D). Blue perimeter stands for water and yellow for chloroform. Black circles highlight the lowest energy conformer and black crosses the position of the correspondent low-energy conformer in the other solvent system.
Figure 8
Figure 8
SMD Tunneling: distribution of IMHB regions based on size and polarity. (A, B) Saquinavir in water (A) and toluene (B). (C,D) CMP 98 in water (C) and toluene (D). Blue perimeter stands for water and orange for toluene.
Figure 9
Figure 9
Conformational Sampling: conformers selection. IMHBs are depicted by dashed ovals. Blue perimeter stands for water and yellow for chloroform. (A) Saquinavir (purple) conformers corresponding to Min and Max 3D PSA in water and chloroform. (B) CMP 98 (green) conformers selected upon 3D PSA in water and chloroform. (C) Superposition (heavy atoms) of minimum energy conformers in chloroform (yellow) and water (blue) for Saquinavir (left) and CMP 98 (right).
Figure 10
Figure 10
SMD Tunneling: conformer selection upon closeness to the center of the density plot (Figure 6). Blue perimeter stands for water and orange for toluene. IMHB are depicted by dashed ovals. (A) Saquinavir (purple). (B) CMP 98 (green).
See this image and copyright information in PMC

References

    1. Lipinski C. A.; Lombardo F.; Dominy B. W.; Feeney P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv Rev. 1997, 23 (1–3), 3–25. 10.1016/S0169-409X(96)00423-1. - DOI - PubMed
    1. Doak B. C.; Over B.; Giordanetto F.; Kihlberg J. Oral druggable space beyond the rule of 5: Insights from drugs and clinical candidates. Chem. Biol. 2014, 21 (9), 1115–1142. 10.1016/j.chembiol.2014.08.013. - DOI - PubMed
    1. Doak B. C.; Kihlberg J. Drug discovery beyond the rule of 5 - Opportunities and challenges. Expert Opin Drug Discovery 2017, 12 (2), 115–119. 10.1080/17460441.2017.1264385. - DOI - PubMed
    1. Sakamoto K. M.; Kim K. B.; Kumagai A.; Mercurio F.; Crews C. M.; Deshaies R. J. Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. U. S. A. 2001, 98 (15), 8554–8559. 10.1073/pnas.141230798. - DOI - PMC - PubMed
    1. Ermondi G.; Garcia-Jimenez D.; Caron G. Protacs and building blocks: The 2d chemical space in very early drug discovery. Molecules 2021, 26, 672.10.3390/molecules26030672. - DOI - PMC - PubMed

Publication types