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Peptide and peptidomimetic libraries

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I am biochemist and I am really very satisfied from this course. I learned a lot from this course. It is very instructional about drug discovery and development. Was this review helpful to you? Sign up for free. My Classes. The PCA data were then used for the construction of PC1 representing size, shape, and polarizability vs. PC2 representing aromatic and conjugation related properties.

Principal moments of inertia analysis was carried out by calculating the lowest energy conformation of compounds 35 — 38 and compound 42 , and each compound from an in-house library of morpholine-derived compounds. Once the lowest energy conformer was calculated, the three principal moments of inertia Ixx, Iyy, Izz and the normalized principal moments of inertia were determined.


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Specifically, the three calculated principal moments of inertia were sorted by ascending magnitude I 1 , I 2 , and I 3. LogP values are computed by using the xLogP3 program Cheng et al. Fsp 3 was calculated as the number of sp 3 hybridized carbon atoms vs. Rotatable bonds were defined as any single bond, not in a ring, bound to a non-terminal heavy i.

Hydrogen bond donors were taken as the sum of all OHs and NHs, and hydrogen bond acceptors were taken as the sum of all oxygen and nitrogen atoms without a formal positive charge, excluding pyrrole nitrogen, heteroaromatic oxygen and higher oxidation states of nitrogen, in agreement with the Lipinski definition Lipinski, In particular, we selected methyl 5-oxomorpholinecarboxylate 25 derived by the application of the Castagnoli-Cushman reaction Dar'in et al. To improve the scaffold complexity and to install quaternary stereocenters on these compounds, we firstly studied the Staudinger reaction Alcaide et al.

In particular, compounds 28 and 29 were transformed into the more reactive acyl chloride derivatives 30 — 31 in order to generate the intermediate ketene more easily and to avoid the formation of amide by-products Scheme 4.

Scheme 4. Synthesis of methyl 5-oxomorpholinecarboxylate 25 and methyl 5-oxomorpholinecarboxylates 28 and 29 and preparation of acyl chloride derivatives 30 and Table 1. Considering that the nucleophilicity of the amine derivatives comprising the imine proved to affect the yields, only aromatic imines were taken into account. Also, as shown in Table 1 , the steric hindrance of both imine and morpholine counterparts resulted in reducing drastically the yield. On the other hand, threonine-derived morpholine 31 was found to be less reactive and unstable, as a consequence of the presence of the methyl group adjacent to the ketene functionality.

Nevertheless, interesting results were obtained as regarding the diastereoselectivity. In fact, despite the four theoretically possible diastereomers, in all cases the cis -products were obtained as a major or single stereoisomer, as shown by 1D and 2D NOESY experiments carried out on spiro compound 37 and 35 see Figures S13 , S In particular, the existence of a NOESY peak between H-3 and the methyl group at C-9 for compound 37 proved the relative configuration as reported in Figure 2. The absence of any correlation between the methyl group and H-7 suggested that the methyl group is oriented in equatorial position.

Although purely indicative, this observation was found to be reasonable for such a constrained structure and was in agreement with the global minimum conformer resulting from molecular modeling calculations Figure 2 , right. Specifically, the calculated distance between H-3 and the CH 3 atoms was 2. Similar structural arrangement was ascertained for compound 35 , with the C-1 carbonyl group pointing toward C-9 and the H-3 showing a strong NOESY correlation with H-9 protons, whereas the same cis -configuration was evinced for the other compounds by comparing the diagnostic signal of the H-3 proton, which appeared as a singlet in an unambiguous region of 1 H-NMR spectrum between 4.

Figure 2. Key NOESY peak Left , and lowest energy conformer Right of compound 37 showing the major stereoisomer resulting from the two newly-generated stereocenters at C-3 and C Unfortunately, when the Staudinger reaction was performed between the acid chloride of methyl 5-oxomorpholinecarboxylate 25 and aromatic imines 32 — 34 , only degradation products were observed. Structure analysis performed by NMR and molecular modeling calculations showed a half-chair conformation for the morpholinone scaffold possessing both the methyl and aryl groups in axial position and with a trans geometry.

Figure 3. The exploration of the chemical space accessed by newly synthesized compounds 35 — 42 , in relation to the pool of morpholine-derived small molecules previously synthesized in our laboratories, was then studied by using different chemoinformatic approaches see Figure 4 for a scaffold tree composed by all the 16 different molecular frameworks present in this library. Figure 4. Morpholine-containing molecular scaffolds of our in-house library. The number of compounds in the library representing each scaffold is displayed in brackets.

A pool of compounds was analyzed, focusing in particular on principal component one PC1 , representing size, shape and polarizability, and the principal component two PC2 , that is a direct expression of aromatic and conjugation related properties, and plotted in a graph Figure 5 , where compounds 35 — 42 are shown as red diamonds, their parent analogs 25 , 28 , and 29 as blue diamonds, and the previously synthesized morpholines as black squares.

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All the library members were found being grouped in four different clusters Figure 5 , I—IV , depending on both the structure of the skeletons and side chain properties. As regarding to the introduction of quaternary stereocenters in the morpholine nucleus, a peculiar effect was found for the Staudinger reaction products. Figure 5. PCA plot resulting from the correlation between PC1 vs.

PC2, showing the positioning in the chemical space of compounds 35 — 42 red diamonds and their parent analog 25 , 28 , and 29 blue diamonds , in relation to an in-house library of morpholine compounds black squares. The ellipses highlight the various compounds subclasses; the compound clusters are numbered as I — IV. As evinced from this graph, morpholine-derived compounds were found to lie along the center-left side of the triangle, as usually observed in the PMI analysis of small molecules.

However, while the Staudinger chemistry performed on bicyclic 3-aza-6,8-dioxabicyclo[3. Also, amide by-products 39 — 41 were found lying closer to the rod-disc axis, as a result of the less three-dimensional character possessed by these structures, when compared to 28 — On the contrary, the effect of the extra methyl group in compound 42 did not prove to change significantly the shape of the morpholine nucleus, as this compound was found to be close to its parent 25 in the PMI plot. Interestingly, the bicyclic compounds based on the 6,8-dioxaazabicyclo[3.

Figure 6. PMI plot showing the skeletal diversity of compounds 35—42 and their parent analogs 25 , 28 , and 29 red diamonds , in relation to an in-house library of morpholine compounds black squares.

Drug Design Today: Large Molecules or Small Molecules?

The ellipses highlight the various compounds subclasses. To gain insight into a chemoinformatic evaluation of our in-house morpholine library, we calculated the saturation index Fsp 3 of each compound collection, as a measure of the molecular complexity Lovering et al.

This value was calculated as the ratio between the number of sp 3 hybridized carbons in the molecule vs.


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  7. Sp 3 -rich DOS-derived small molecule collections proved to be more selective and more effective in binding to specific targets, as compared to analog small molecule libraries with lower Fsp 3 ratio Clemons et al. However, the Staudinger ketene-imine reaction, despite the possibility to introduce a quaternary stereocenter in the molecule, proved not to be a good strategy in terms of improving the Fsp 3 ratio of the overall molecule, since it introduced a high number of sp 2 carbon atoms due to the presence of aromatic appendages.


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    In fact, the Fsp 3 of starting compounds 28 and 29 respectively 0. Figure 7. Left Fraction of compounds morpholines in blue, blockbuster drugs in red with different Fsp 3 value, subdivided into 5 different ranges.

    Chemical space as a source for new drugs

    In particular, we evaluated the lipophilicity and the molecular weight as key parameters to achieve good solubility, membrane permeability and subsequent oral bioavailability, by plotting clogP values calculated as the logarithm of the partition coefficient between n-octanol and water and the molecular weight of each library member in a graph Figure 8 , left. This was evinced for compounds where morpholine was installed in a pentapeptide, or in the case of few bicyclic or morpholines characterized by a large number of aromatic substituents.

    Similarly, Veber et al. In particular, the introduction of the nitrogen atom brought another hydrogen bond acceptor to the molecule moving from 5 to 6 and the number of rotatable bonds increased from 4 to 5 or 6, depending on the imine counterpart. Figure 8. Left cLogP vs. The development of new peptidomimetic scaffolds useful to address protein-protein interactions is still a growing field of medicinal chemistry and chemical biology.

    This approach requires efficient synthetic processes able to produce high-quality small molecule collections, as in the case of the use of Diversity Oriented Synthesis DOS strategies, especially starting from amino acid and sugar derivatives, to produce polyfunctional and sp 3 -rich building blocks. Our efforts in this field are focused on the generation of different peptidomimetic compounds around the morpholine nucleus, as this heterocycle is contained in many different bioactive molecules.

    This approach proved to be valuable, especially when assessing the structural diversity and complexity of these new compounds in comparison with morpholine-derived small molecules previously synthesized in our laboratories, by analyzing the populated chemical space. In fact, both PCA Principal Component Analysis and PMI Principal Moment of Inertia analysis revealed that the Staudinger ketene-imine reaction proved to shift the serine and threonine-derived morpholineone compounds in new areas of the chemical space, assessing a relevant change of positions, hardly achieved by using other synthetic approaches.

    Indeed, several applications in medicinal chemistry projects demonstrated over the years the value of morpholine as a scaffold for peptidomimetic design and drug discovery. AT and EL conceived the research. EL and RI carried out the synthesis. EL carried out the chemoinformatics analyses. AT carried out the molecular modeling calculations. AT and GM supervised the work.

    EL and AT wrote the paper.