Targeting bioactive chemical space with a small natural products library: Expanding diversity and predictability

JL von Salm; D Santiago; NG Wilson; L Calcul; DE Kyle; WC Guida; BJ Baker

doi:10.1055/s-0035-1556375

Planta Medica, Table of Contents

Targeting bioactive chemical space with a small natural products library: Expanding diversity and predictability

JL von Salm ¹^,², D Santiago ¹, NG Wilson ³, L Calcul ¹^,², DE Kyle ⁴, WC Guida ¹^,²^,⁵, BJ Baker ¹^,²

¹Department of Chemistry
²Center for Drug Discovery & Innovation, University of South Florida, Tampa, FL 33620, USA
³Western Australia Museum, Perth, Western Australia, Australia
⁴Department of Global Health, University of South Florida, Tampa, FL 33620, USA
⁵H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33620, USA

Abstract

Diverse compound libraries have become a necessity to drug discovery efforts around the world. Target specific computational methods and high-throughput screening programs have aided the search for bioactive compounds, however, inefficiencies remain for neglected and tropical diseases. Detailed knowledge of mechanisms of action and target proteins is limited for parasitic diseases like malaria and leishmaniasis. In order to effectively lead research programs in these areas, our lab has developed a small compound library with diversity that mimics the NCI Diversity Set and the AntiMarin natural products database. Specific activity exhibited by each compound against Plasmodium falciparum and Leishmania donovani has been overlain to create activity “hotspots”, which we hope to improve activity prediction methods for unknown natural products isolated in the future. Limitations in diversity remain in all three libraries, and appear to have properties resembling small (MW < 400) hydrophobic molecules like terpenes. Here we use active antileishmanial terpenoids isolated from Antarctic marine organisms as models to show expansion of overall diversity and future predictability of the library as a bioassay dereplication tool.