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

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.

Application of the anthraquinone drug rhein as an axial ligand in bifunctional Pt(IV) complexes to obtain antiproliferative agents against human glioblastoma cells.

Octahedral Pt(IV) prodrugs are an effective way to combine cisplatin-like moieties and a second drug to obtain selective and stimuli responsive bifunctional antiproliferative compounds. Recently, two bifunctional Pt(IV) complexes have shown interesting in vitro and in vivo effects in glioblastoma, the most aggressive primary brain tumor. An interesting observation indicates that 4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid (rhein) can inhibit in vivo glioma tumor progression. Furthermore, a prodrug in which cisplatin was combined with two molecules of rhein showed a potency higher than that of cisplatin toward cisplatin-resistant lung carcinoma cells. However, the high lipophilicity of this type of complex affects their solubility and bioavailability. To overcome these limits, in the present work, three Pt(IV) derivatives were obtained by differently linking one molecule of rhein and one acetato ligand at the axial position to a cisplatin core. The complexes proved to be similar to or more potent than the parent cisplatin and rhein, and the reference drug temozolomide on two human glioblastoma cell lines (U87-MG and T98G). They retained their activity under hypoxia and caused a significant reduction in the motility of both cell lines, which can be related to their ability to inhibit MMP2 and MMP9 matrix metalloproteinases. Finally, physicochemical and computational studies indicated that these Pt(IV) derivatives are more prone than rhein to cross the blood-brain barrier.

Managing Experimental 3D Structures in the Beyond-Rule-of-5 Chemical Space: The Case of Rifampicin.

The beyond-Rule-of-5 (bRo5) chemical space is a source of new oral drugs and includes large and flexible compounds. Because of their size and conformational variability, bRo5 molecules assume different privileged conformations in the compartments of human body, i. e., they can exhibit chameleonic properties. The elucidation of the ensemble of 3D structures explored by such molecules under different conditions is therefore critical to check the role played by chameleonicity to modulate cell permeability. Here we characterized the conformational ensembles of rifampicin, a bRo5 drug, in polar and nonpolar solvents and in the solid state. We performed NMR experiments, analyzed their results with a novel algorithm and set-up a pool of ad hoc in silico strategies to investigate crystallographic structures retrieved from the CSD. Moreover, a polarity descriptor often related to permeability (SA-3D-PSA) was calculated for all the conformers and its variation with the environment analyzed. Results showed that the conformational behavior of rifampicin in solution and in the solid state is not superposable. The identification of dynamic intramolecular hydrogen bonds can be assessed by NMR spectroscopy but not by X-ray structures. Moreover, SA-3D-PSA revealed that dynamic IMHBs do not provide rifampicin with chameleonic properties. Overall, this study highlights that the peculiarity of rifampicin, which is cell permeable probably because of the presence of static IMHBs but is devoid of any chameleonic behavior, can be assessed by a proper analysis of experimental 3D structures.

Pt(iv) complexes based on cyclohexanediamines and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid: synthesis, characterization, cell penetration properties and antitumor activity.

The Pt(iv) complexes based on (SP-4-2)-dichlorido(cyclohexane-1,4-diamine)platinum(ii) (kiteplatin) and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid (POA) were investigated. Since POA contains a chiral carbon, all the possible Pt(iv) isomers were prepared and characterized, and their antiproliferative activity on six cancer cell lines was compared with that of the corresponding Pt(iv) complexes containing the cyclohexane-1R,2R-diamine equatorial ligand. To justify the very good antiproliferative activity (nanomolar IC50), the polarity, lipophilicity, permeability, and cell accumulation of the complexes were studied. Overall, the two series of Pt(iv) complexes showed similar cell penetration properties, being significantly better than that of the Pt(ii) reference compounds. Finally, a representative compound of the whole set of complexes (i.e., that based on cyclohexane-1R,2R-diamine and racemic POA) was tested in vivo on mice bearing Lewis lung carcinoma, showing good tumor growth inhibition with negligible body weight loss.

Novel small molecule protein arginine deiminase 4 (PAD4) inhibitors.

Protein arginin deaminase 4 (PAD4) is a calcium dependent enzyme which catalyses the conversion of peptidyl-arginine into peptidyl-citrulline and is implicated in several diseases such as rheumatoid arthritis (RA) and cancer. Herein we report the discovery of novel small-molecule, non peptidic PAD4 inhibitors incorporating primary/secondary guanidine moieties.