The paper describes the generation of four types of three-dimensional molecular field descriptors or 'field points' as extrema of electrostatic, steric, and hydrophobic fields. These field points are used to define the properties necessary for a molecule to bind in a characteristic way into a specified active site. The hypothesis is that compounds showing a similar field point pattern are likely to bind at the same target site regardless of structure. The methodology to test this idea is illustrated using HIV NNRTI and thrombin ligands and validated across seven other targets. From the in silico comparisons of field point overlays, the experimentally observed binding poses of these ligands in their respective sites can be reproduced from pairwise comparisons.

FieldScreen, a ligand-based Virtual Screening (VS) method, is described. Its use of 3D molecular fields makes it particularly suitable for scaffold hopping, and we have rigorously validated it for this purpose using a clustered version of the Directory of Useful Decoys (DUD). Using thirteen pharmaceutically relevant targets, we demonstrate that FieldScreen produces superior early chemotype enrichments, compared to DOCK. Additionally, hits retrieved by FieldScreen are consistently lower in molecular weight than those retrieved by docking. Where no X-ray protein structures are available, FieldScreen searches are more robust than docking into homology models or apo structures.

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 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.

No abstract

The synthesis of [Nbenzyl-N-(Nubenzyloxycarbonyl-L-asparaginyl) hydrazino]sulfonyl-L-prolyl-Lisoleucyl-L-valine methyl ester 4, a potential HIV-1 proteinase inhibitor, is described.We recently defined feasible synthetic approaches to azasulfonamidopeptides 1, ' which are a novel class of analogues for Boc-Asn(Trt)-OHL Boc-Asn(Trt)-OMe

The title compounds, a novel class of peptide analogues in which an a-amino acid residue is replaced by a hydrazine-1.2-diyl sulfonyl group -NHNRSO,-, are of potential interest as proteinase inhibitors. Synthetic approaches to such compounds and the X-ray molecular structures of two examples (1 6 and 28) are reported.

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.