David iam Will

PNA: Synthetic Polyamide Nucleic Acids with Unusual Binding Properties

The astonishing discovery that peptide nucleic acids (PNAs, B=nucleobase), in spite of their drastic structural difference to natural DNA, are better nucleic acid mimetics than many other oligonucleotides has resulted in an explosion of research into this class of compounds. The synthesis, physical properties, and biological interactions of PNAs as well as their chimeras with DNA and RNA are summarized here.

Evidence for CCl/CBr⋅⋅⋅π Interactions as an Important Contribution to Protein–Ligand Binding Affinity†

Attractive chlorine: Noncovalent interactions between chlorine or bromine atoms and aromatic rings in proteins open up a new method for the manipulation of molecular recognition. Substitution at distinct positions of two factor Xa inhibitors improves the free energy of binding by interaction with a tyrosine unit. The generality of this motif was underscored by multiple crystal structures as well as high-level quantum chemical calculations (see picture).

The synthesis of polyamide nucleic acids using a novel monomethoxytrityl protecting-group strategy

Abstract The preparation of novel monomethoxytrityl (Mmt) protected monomers for the synthesis of polyamide nucleic acids (PNAs) is described. The use of base-labile acyl-type nucleobase protecting groups and of a succinyl-linked solid-support offers a synthetic strategy similar to standard oligonucleotide synthesis conditions. This strategy has been successfully applied for the synthesis of PNAs of mixed base sequence.

Novel synthetic routes to PNA monomers and PNA-DNA linker molecules

Abstract Novel methods for the preparation of monomethoxytrityl (Mmt) protected aminoethylglycine building blocks and dimethoxytrityl (Dmt) protected hydroxyethylglycine derivatives useful for the synthesis of polyamide nucleic acids (PNAs) and PNA/DNA chimeras are described. The protecting group strategy employed for PNA monomer synthesis produces easily isolable intermediates, minimizes chromatographic purification, and is suitable for large-scale monomer synthesis.

Fragment Deconstruction of Small, Potent Factor Xa Inhibitors: Exploring the Superadditivity Energetics of Fragment Linking in Protein-Ligand Complexes.

Predictable thermodynamic additivity is one of the cornerstones of classical covalent chemistry, allowing accurate calculation of energy terms for complete processes by addition of terms for individual components. However this principle breaks down in complex noncovalent systems, such as biological systems, in which the energetics of individual components are not truly independent of each other. This complicates predicting protein structure and folding and, the focus of this work, the prediction of ligand binding to proteins. Molecular recognition in protein–ligand complexes predominantly occurs through multiple noncovalent interactions, whereas their contribution to the total free-energy of binding (DG) is often unevenly distributed over the contact interface. The identification of ligands as “molecular anchors” for high affinity regions in proteins (“hot spots”) is fundamental for fragment-based drug discovery, 3] indicating the similarity of ligandand protein-centric concepts. Often highaffinity ligands encompass more than one fragment in proximal protein sites; in a few cases, individual fragments in two neighboring sites could be linked to result in high binding affinity. Ideally, the DG of linked fragments should be significantly greater than the sum of DG increments from each fragment. This overproportional increase (“superadditivity”) is attributed to the fact that each fragment loses a significant part of its rigid body rotational and translational entropy upon complex formation. Thus, the sum of DG for two fragments includes two unfavorable rigid body entropy barrier terms, whereas the joined molecule is only affected by one of these terms. Any ligand has to overcome this barrier because of entropy loss upon association to its site. The nonadditivity for DG contributions is defined as linker coefficient E corresponding to the difference between the sums of fragment affinity and the final ligand [Eq. (1)]. DGfinal 1⁄4 DGfrag1 þ DGfrag2 þ DGlink with DGlink 1⁄4 R T ln E ð1Þ

PNAs: synthetische Polyamidnucleinsäuren mit außergewöhnlichen Bindungseigenschaften

Auserst uberraschend war die Erkenntnis, das Peptidnucleinsauren (PNAs, B=Nucleobase) trotz ihrer drastisch vom naturlichen DNA-Ruckgrat abweichenden Struktur besser als die meisten Oligonucleotidderivate als Nucleinsauremimetica genutzt werden konnen. Die Synthese, physikalischen Eigenschaften und biologischen Wechselwirkungen sowohl der PNAs als auch ihrer Chimaren mit DNA und RNA werden hier zusammenfassend beschrieben.

αvβ3 Antagonists Based on a Central Thiophene Scaffold

Abstract A series of novel, highly potent αvβ3 antagonists based on a thiophene scaffold and containing an acylguanidine as an Arg-mimetic is described. A number of structural features, such as cyclic versus open guanidine and a variety of lipophilic side chains, carbamates, sulfonamides and β-amino acids were explored with respect to inhibition of αvβ3 mediated cell adhesion and selectivity versus αIIbβ3 binding. In addition, compound 19 was found to be active in the TPTX model of osteoporosis.