p38 MAP kinase has received considerable interest in the pharmaceutical industry and remains a valid and interesting target for the treatment of inflammation. To discover novel p38 inhibitors, we applied the ligand-based virtual screening technique, FieldScreen, to 1.2 million commercially available compounds. Fifty-eight diverse compounds were selected for biological analysis, using molecular field similarity to known inhibitors, while explicitly removing any structure that shared a scaffold with previously reported p38 inhibitors. Of these, 11 (19%) showed >or=20% inhibition of p38 at 10 microM. We chose to prepare analogues of two distinct chemical series resulting in a potential lead compound with pIC(50) of 6.4. Modeling of SAR using FieldAlign, a ligand alignment protocol, was used to rationalize the SAR of the series of thiadiazole based inhibitors.
The analysis of activity landscapes and activity cliffs is a widely used method to locate critical regions of SAR. Knowledge of what changes in a series of molecules caused unexpectedly large changes in affinity allows the chemist to focus on the molecular features which are crucial for activity. We examine the usefulness of activity cliff analysis with a metric based on 3D shape and electrostatic similarity, utilizing a ligand-based alignment method. We demonstrate that 3D activity cliff analysis is complementary to the more usual 2D fingerprint-based methods, in that each finds cliffs that the other misses. Moreover, we show that analysis of the activity landscape in the context of a consensus 3D alignment allows the source of the activity cliff to be investigated in terms of the effect that a structural change has on the steric and electrostatic properties of a molecule. The technique is illustrated with two set of compounds with activity against acetylcholinesterase and dipeptidyl peptidase.
<p>The analysis of activity landscapes and activity cliffs is a widely used method to locate critical regions of SAR. Knowledge of what changes in a series of molecules caused unexpectedly large changes in affinity allows the chemist to focus on the molecular features which are crucial for activity. We examine the usefulness of activity cliff analysis with a metric based on 3D shape and electrostatic similarity, utilizing a ligand-based alignment method. We demonstrate that 3D activity cliff analysis is complementary to the more usual 2D fingerprint-based methods, in that each finds cliffs that the other misses. Moreover, we show that analysis of the activity landscape in the context of a consensus 3D alignment allows the source of the activity cliff to be investigated in terms of the effect that a structural change has on the steric and electrostatic properties of a molecule. The technique is illustrated with two set of compounds with activity against acetylcholinesterase and dipeptidyl peptidase.</p>
The preparation of side-chain-to-side-chain-cyclised peptides through lactam bridge formation requires orthogonal protecting groups for side-chain amino and carboxylate functionalities. Use of the 4-{N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino}benzyl ester (Dmab) group for this role in the protection of the glutamyl side-chain resulted in the formation of unexpected side-products. During synthesis of fully protected peptide targets, Nα-pyroglutamyl chain-terminated peptides were observed. Pyroglutamyl peptides were not observed in analogous peptides synthesised using the traditional tert-butyl ester protecting group. Selective removal of the Dmab group proceeds through a two-stage procedure, hydrazinolytic cleavage of the dimedone moiety followed by 1,6-elimination of the resulting peptide-glutamyl 4-aminobenzyl ester. The latter reaction is sufficiently slow to allow isolation of the transiently stable glutamyl derived 4-aminobenzyl ester peptide. Attempted side-chain-to-side-chain cyclisation (through orthogonally protected Glu and Lys residues) of peptides prepared via Glu(ODmab) failed and led to modification of the Lys Nε-amino group when 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) was used as carboxy-activating reagent. Analogous peptides prepared utilising allyl side-chain protection for glutamyl residues were successfully cyclised using HBTU.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The question of how and why a small molecule binds to a protein is central to ligand-based drug discovery. The traditional way of approaching these questions is pharmacophore analysis. However, pharmacophores as usually applied lack quantitation and subtlety. An improvement is to consider the electrostatic and steric fields of the ligand directly. Molecular fields provide a rich view of the potential interactions that a molecule can make and can be validated through experimental data on molecular interactions and through quantum mechanics calculations. A technique is presented in this review for comparing molecules using molecular fields and assigning similarity scores. This high information content method can be used to align molecules for SAR analysis, to determine the bioactive conformation from ligand data, and to screen large libraries of compounds for structurally unrelated actives. An extension to allow interactive exploration of chemistry space via bioisostere analysis is also reviewed. Examples from the literature showing the success of these methods are presented, and future directions discussed.
We wanted to discover novel chemotypes for 2 targets which lacked x-ray data, CCK2 and 11beta-HSD1. Our approach was to undertake ligand-based virtual screening using the molecular fields of active compounds as our template to define activity. Our hypothesis was that the field pattern of an active molecule describes its key binding features and molecules with a similar field have a high probability of showing the same biological activity.
For CCK2, we took the 2D structures of 3 active ligands and used FieldTemplater to identify the bioactive conformations which were used as templates for virtual screening. Twenty-seven hits were found from 88 compounds tested.
There was no x-ray structure for 11beta-HSD1 at the time of this study, so using structural information from related enzymes, we generated a cut-down version of cortisone and used this as our virtual screening template. Subsequent testing of 410 compounds identified 23 hits in 4 chemical series. Two of these series were subsequently patented by pharmaceutical companies and one has now been patented by our co-workers.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The title compounds, a novel class of peptide analogues in which an α-amino acid residue is replaced by a hydrazine-1, 2-diyl sulfonyl group -NHNRSO2-, are of potential interest as proteinase inhibitors. Synthetic approaches to such compounds and the X-ray molecular structures of two examples (16 and 28) are reported.
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