Piotr F. J. Lipiński

Chirality Measures of α-Amino Acids

To measure molecular chirality, the molecule is treated as a finite set of points in the Euclidean R(3) space supplemented by k properties, p(1)((i)), p(2)((i)), ..., p(k)((i)) assigned to the ith atom, which constitute a point in the Property P(k) space. Chirality measures are described as the distance between a molecule and its mirror image minimized over all its arbitrary orientation-preserving isometries in the R(3) × P(k) Cartesian product space. Following this formalism, different chirality measures can be estimated by taking into consideration different sets of atomic properties. Here, for α-amino acid zwitterionic structures taken from the Cambridge Structural Database and for all 1684 neutral conformers of 19 biogenic α-amino acid molecules, except glycine and cystine, found at the B3LYP/6-31G** level, chirality measures have been calculated by a CHIMEA program written in this project. It is demonstrated that there is a significant correlation between the measures determined for the α-amino acid zwitterions in crystals and the neutral forms in the gas phase. Performance of the studied chirality measures with changes of the basis set and computation method was also checked. An exemplary quantitative structure–activity relationship (QSAR) application of the chirality measures was presented by an introductory model for the benchmark Cramer data set of steroidal ligands of the sex-hormone binding globulin.

Design, synthesis and in vitro biological evaluation of a small cyclic peptide as inhibitor of vascular endothelial growth factor binding to neuropilin-1.

Neuropilin-1 (NRP-1) is a co-receptor of VEGFR (vascular endothelial growth factor receptor), but it is also suggested that NRP-1 in tumour cells may serve as a separate receptor for VEGF165. Therefore molecules interfering with VEGF165 binding to NRP-1 seem to be promising candidates as new anti-angiogenic and anti-tumour drugs. Here, we report the design, synthesis, biological evaluation and molecular modelling of the small cyclic peptide, which shows a good inhibitory effect on VEGF165/NRP-1 binding (IC50=0.18μM). The reported compound could be considered as one of the smallest cyclic peptides (MW=510) interfering with VEGF165/NRP-1 binding presented up to now.

Local chirality measures in QSPR : IR and VCD spectroscopy

The paper presents the first successful attempt at obtaining Quantitative Structure–Property Relationships (QSPR) of vibrational spectra parameters with chirality measures. The local chirality measures defined based on the Sinister–Rectus Chirality and Continuous Chirality approaches were calculated and intercompared for selected fragments of 28 5-substituted 1-cyano-1H-indenes. It appeared that there is no correlation between global and local variants of the chirality measures which additionally are less linearly interdependent than the global ones. The obtained local chirality measures were correlated with the frequency, IR and VCD intensity of the ν(CN) and ν(C*H) stretching modes. It was proven that vibrational spectroscopy gives some information on the local chirality of molecules. Especially, some well-isolated VCD bands could be a proper experimental, physical measure of local chirality. It was also demonstrated that some local chirality measures are highly collinear with the substituent effect descriptors σp and pEDA(I), showing that the electronic properties of a substituent may significantly influence the chirality of an aromatic system.

On splitting of the NICS(1) magnetic aromaticity index

The NICS(1) magnetic aromaticity index is split into NICS(1) and NICS(−1) indices when the points 1 A above and below the ring center are inequivalent by symmetry. The two indices characterize the aromaticity of the two ring faces rather than the ring itself. We propose new NICS(1) co-indices to complete aromaticity analysis.

Structure-activity relationship study of a small cyclic peptide H-c[Lys-Pro-Glu]-Arg-OH: a potent inhibitor of Vascular Endothelial Growth Factor interaction with Neuropilin-1

Inhibition of angiogenesis is one of the most promising approaches in anticancer therapy. It was recently suggested that Neuropilin-1 (NRP-1) in tumour cells may serve as a separate receptor for Vascular Endothelial Growth Factor-165 (VEGF165) which is one of the main pro-angiogenic agents in the organism. Therefore molecules inhibiting VEGF165 binding to NRP-1 could be potential candidates for new antiangiogenic and anticancer drugs. Here we present a structure-activity relationship study of the peptide H-c[Lys-Pro-Glu]-Arg-OH which showed high inhibitory effect on VEGF165/NRP-1 binding (IC50=0.18μM) in our previous study. We report the design, synthesis, in vitro assays and docking analysis of four small cyclic peptides (14-,15-membered ring) and one bigger cyclic compound (30-membered ring). Our study shows that both the ring size and configuration of amino acid residues present in the structure are crucial for high inhibitory effect.

Substituent effect in theoretical ROA spectra

The first systematic study on substituent effect in theoretical VCD spectral parameters is reported. The VCD spectra of 5-substituted indenes revealed strong correlations of ν(C*H) and ν(CN) VCD intensities with σp or pEDA(I) descriptors. We also report correlations of VCD intensity factors as well as VCD sign-change with substituent.

Conformational latitude – activity relationship of KPPR tetrapeptide analogues toward their ability to inhibit binding of vascular endothelial growth factor 165 to neuropilin-1

Neuropilin‐1 (NRP‐1) has been found to be overexpressed in several kinds of malignant tumors, and it is postulated that in pathological angiogenesis, its interaction with the vascular endothelial growth factor 165 (VEGF165) leads to progression of tumor vascularization and growth. Herein, we present synthesis and in vitro evaluation of tetrapeptides with the general sequence KxxR, where xx represents two canonical amino acid residues or a single amino acid possessing hydrocarbon backbone. All synthesized compounds were found to be inhibitors of VEGF165/NRP‐1 interactions. The rationale behind their design was to elucidate the relationship between the xx flexibility and their inhibitory activity. Detailed molecular dynamics simulations for all synthesized compounds have been performed. A clear and quantitative relationship was found in the peptide analogues: the more flexible is the xx, the less active the analogue is. But surprisingly, highly flexible peptidomimetics with non‐natural amino acids (NH2‐(CH2)n‐COOH; n = 4,5) residues used possessed higher inhibitory activity than it was expected. Our molecular dynamics study of inhibitor/NRP‐1 complexes provides convincing explanations of divergence in the observed inhibitory activity; thus, it might give indication for design of the next generation NRP‐1 inhibitors. Copyright

Structure-activity relationship study of tetrapeptide inhibitors of the Vascular Endothelial Growth Factor A binding to Neuropilin-1

HIGHLIGHTS13 tetrapeptides were synthesized, tested for inhibitory activity on VEGF165/NRP‐1 binding and modeled by molecular dynamics.Arg or Har in 1st position allow optimal interactions with NRP‐1 (length and delocalized charge of guanidinium group).Rigidity of central part of molecule should be partially preserved, changes in position 2 more favorable than in position 3.Har‐Dab‐Pro‐Arg, exhibits a submicromolar IC50, is almost 10 times stronger than a reference inhibitor A7R.the results give an important insight into structural requirements for high inhibitory activity on VEGF165/NRP‐1 interaction. ABSTRACT Neuropilin‐1 is considered as one of the key receptors responsible for signaling pathways involved in pathological angiogenesis necessary for tumor progression, therefore targeting of VEGF165 binding to NRP‐1 could be a relevant strategy for antiangiogenic treatment. It was shown before that the VEGF165/NRP‐1 interaction can be inhibited by short tetrapeptides with K/RXXR sequence. Here, we present a structure–activity relationship study of the systematic optimization of amino acid residues in positions 1–3 in the above tetrapeptides. All the 13 synthesized analogs possessed C‐terminal arginine that is a necessary element for interaction with NRP‐1. The obtained results of the inhibitory activity and modeling by molecular dynamics indicate that simultaneous interactions of the basic amino acid residues in position 1 and 4 (Arg) with Neuropilin‐1 are crucial and their cooperation strongly affects the inhibitory activity. In addition, the binding strength is modulated by the flexibility of the peptide backbone (in the central part of the peptide), and the nature of the side chain of the amino acids at the second or third position. A dramatic decrease in the activity to the receptor is observed in flexible derivatives that are missing proline residues. The results described in this paper should prove useful for future studies aimed at establishing the best pharmacophore for inhibitors of VEGF165 binding to NRP‐1.

Hydrazone Linker as a Useful Tool for Preparing Chimeric Peptide/Nonpeptide Bifunctional Compounds

The area of multitarget compounds, joining two pharmacophores within one molecule, is a vivid field of research in medicinal chemistry. Not only pharmacophoric elements are essential for the design and activity of such compounds, but the type and length of linkers used to connect them are also crucial. In the present contribution, we describe compound 1 in which a typical opioid peptide sequence is combined with a fragment characteristic for neurokinin-1 receptor (NK1R) antagonists through a hydrazone bridge. The compound has a high affinity for μ- and δ-opioid receptors (IC50= 12.7 and 74.0 nM, respectively) and a weak affinity for the NK1R. Molecular modeling and structural considerations explain the observed activities. In in vivo test, intrathecal and intravenous administrations of 1 exhibited a strong analgesic effect, which indicates potential BBB penetration. This letter brings an exemplary application of the hydrazone linker for fast, facile, and successful preparation of chimeric compounds.

Structural Insights into σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations

Despite considerable advances over the past years in understanding the mechanisms of action and the role of the σ1 receptor, several questions regarding this receptor remain unanswered. This receptor has been identified as a useful target for the treatment of a diverse range of diseases, from various central nervous system disorders to cancer. The recently solved issue of the crystal structure of the σ1 receptor has made elucidating the structure–activity relationship feasible. The interaction of seven representative opioid ligands with the crystal structure of the σ1 receptor (PDB ID: 5HK1) was simulated for the first time using molecular dynamics (MD). Analysis of the MD trajectories has provided the receptor–ligand interaction fingerprints, combining information on the crucial receptor residues and frequency of the residue–ligand contacts. The contact frequencies and the contact maps suggest that for all studied ligands, the hydrophilic (hydrogen bonding) interactions with Glu172 are an important factor for the ligands’ affinities toward the σ1 receptor. However, the hydrophobic interactions with Tyr120, Val162, Leu105, and Ile124 also significantly contribute to the ligand–receptor interplay and, in particular, differentiate the action of the agonistic morphine from the antagonistic haloperidol.