Validating the Use of Rational Modification of Compounds to Reduce P-gp Efflux

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In both the Central nervous system (CNS) as well as Oncology small molecule drug discovery programs, efflux due to P-glycoprotein (P-gp) could be a deterrent during the discovery phase to obtain in vitro or in vivo pharmacological readouts. Several different strategies have been utilized in the past in order to overcome efflux by P-gp, many of which have been described in a recent article [5] from our labs. We describe the use of Induced-fit docking (IFD) of matched pairs (pairs of molecules modified by a single group) in order to demonstrate that a change in the IFD score, destabilizing the complex, will afford a molecule with less P-gp efflux potential. In a particular discovery program, several iterations might need to be implemented after examining the IFD lowest scored pose to obtain a molecule in that chemical series without P-gp efflux. Examples of such an effort are currently underway and will be published shortly. This summary describes therefore what we consider, a validation of a unifying approach to obtaining molecules with low to no p-gp efflux potential.