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Commentary Open Access
Volume 6 | Issue 1 | DOI: https://doi.org/10.33696/Pharmacol.6.054

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

  • 1Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, California 94158, United States
  • 2Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, California 94158, United States
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Corresponding Author

Jay Conrad, Jay.Conrad@ucsf.edu; Roy J Vaz, Roy.Vaz@ucsf.edu

Received Date: June 21, 2024

Accepted Date: June 28, 2024

Abstract

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.

Keywords

P-gp, MDR1, Blood-brain barrier, Kp, CNS penetration, P-glycoprotein, Drug interaction, CADD

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