Enhancement of P-gylcoprotein modulators of arylmethylamine-phenyl derivatives: an integrative modeling approach

Abstract

Multidrug resistance (MDR) plays a crucial role in the failure of cancer treatment with chemotherapeutic agents. In order to overcome the MDR, we have developed both 2D and 3D-QSAR models to enhance the structural requirement for P-gp inhibitors. In this work, hologram quantitative structure–activity relationship (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of arylmethylamine-phenyl derivatives of P-gp inhibitors. The best predictions were obtained for HQSAR model (q 2 = 0.645, r 2 = 0.772), CoMFA model (q 2 = 0.577, r 2 = 0.917), and CoMSIA model (electrostatic, and H-bond donor) (q 2 = 0.610, r 2 = 0.923). Statistical parameters from the generated QSAR models indicated that the data is well fitted and have high predictive ability. HQSAR result showed that donor and acceptor descriptors play an important role in P-gp activity, and methoxy group on the A-ring at R1 position is necessary for increasing activity. The CoMFA and CoMSIA models predicted that steric, electrostatic, and H-bond donor parameters are important for activity toward P-gp. Our theoretical results could be useful to design novel and more potent P-gp derivatives.