Biomedical subjects

John P Overington

Publications and source records attributed to John P Overington.

4 recordsLinked to original sources

PubMed2006

Can we rationally design promiscuous drugs?

Structure-based drug design is now used widely in modern medicinal chemistry. The application of structural biology to medicinal chemistry has heralded the "rational drug design" vision of discovering exquisitely selective ligands. However, recent advances in post-genomic biology are indicating that polypharmacology may be a necessary trait for the efficacy of many drugs, therefore questioning the "one drug, one target" assumption of current rational drug design. By combining advances in chemoinformatics and structural biology, it might be possible to rationally design the next generation of promiscuous drugs with polypharmacology.

Cluster Analysis↗

PubMed2006

How many drug targets are there?

For the past decade, the number of molecular targets for approved drugs has been debated. Here, we reconcile apparently contradictory previous reports into a comprehensive survey, and propose a consensus number of current drug targets for all classes of approved therapeutic drugs. One striking feature is the relatively constant historical rate of target innovation (the rate at which drugs against new targets are launched); however, the rate of developing drugs against new families is significantly lower. The recent approval of drugs that target protein kinases highlights two additional trends: an emerging realization of the importance of polypharmacology, and also the power of a gene-family-led approach in generating novel and important therapies.

Drug Approval↗

PubMed2004

PDBLIG: classification of small molecular protein binding in the Protein Data Bank.

It is known that proteins can adopt different folds while sharing similar features for recognition of similar substrates or ligands, for example, in the binding sites of enzyme cofactors such as ATP. On the other hand, proteins that have highly flexible binding sites or belong to large and diverse protein families can bind structurally dissimilar ligands, as, for example, in the case of the matrix metalloprotease family. We have developed a database, PDBLIG, that classifies protein domains and ligands. The information stored includes each protein's function, domain class(es), which ligand(s) it binds, and so on. The database can provide valuable knowledge for drug discovery, supporting the answering of questions such as whether the same drug molecule can bind different target protein families and whether these families are related functionally or structurally, which ligand classes (such as metabolites or organic molecules) bind to a particular protein family and whether the ligands are druglike, and which target families bind a wide variety of ligands and whether different ligands are associated with different subfamilies.

Binding Sites↗

PubMed2002

Prioritizing the proteome: identifying pharmaceutically relevant targets.

Considerable attention is now being placed on prioritizing the proteome as the point of delivery for genomic information. Some of the challenges faced in prioritizing efforts from a pharmaceutical perspective, when presented with an incomplete proteome picture, are described. Examples of pharmaceutically relevant proteins are used to illustrate an informatics-based analysis of the proteome using knowledge of known drug targets. We show how results can be maximized by linking informatics approaches to experimental techniques and describe methods that can be used for prioritization within unprecedented protein families using, for example, single nucleotide polymorphism data and knowledge of disease pathways.

Drug Design↗