An in vitro toolbox to accelerate anti-malarial drug discovery and development 

23 jul 2020

Susan A. Charman, Alice Andreu, Helena Barker, Scott Blundell, Anna Campbell, Michael Campbell, Gong Chen, Francis C. K. Chiu, Elly Crighton, Kasiram Katneni, Julia Morizzi, Rahul Patil, Thao Pham, Eileen Ryan, Jessica Saunders, David M. Shackleford, Karen L. White, Lisa Almond, Maurice Dickins, Dennis A. Smith, Jörg J. Moehrle, Jeremy N. Burrows, Nada Abla Malaria Journal


Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles.


Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC–MS/MS.