ABSTRACT
The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, Plasmodium falciparum, by targeting PfATP4, an essential ion pump on the parasite surface. The structure of PfATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of PfATP4 inhibitors, thereby reducing project costs associated with the synthesis of inactive compounds. Competition participants could see all entries as they were submitted. In the final round, featuring private sector entrants specializing in machine learning methods, the best-performing models were used to predict novel inhibitors, of which several were synthesized and evaluated against the parasite. Half possessed biological activity, with one featuring a motif that the human chemists familiar with this series would have dismissed as "ill-advised". Since all data and participant interactions remain in the public domain, this research project "lives" and may be improved by others.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Calcium-Transporting ATPases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Models, Biological , Humans , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Structure-Activity RelationshipABSTRACT
The ability to perform an exploratory search and retrieval of relevant documents from a large collection of domain-specific documents is an important requirement both in the field of medicine and other areas. In this paper, we present a unsupervised distributional clustering technique called SOPHIA. SOPHIA provides a semantically meaningful visual clustering of the document corpus in conjunction with an intuitive interactive search facility. We assess the effectiveness of SOPHIA's cluster-based information retrieval for the MEDLINE testset collection known as OHSUMED.