2013 http://informahealthcare.com/xen ISSN: 0049-8254 (print), 1366-5928 (electronic) Xenobiotica, Early Online: 1–9 ! 2013 Informa UK Ltd. DOI: 10.3109/00498254.2013.791003 REVIEW ARTICLE Structure–activity relationships and in silico models of P-glycoprotein (ABCB1) inhibitors Hongming Liu*, Zhiguo Ma*, and Baojian Wu Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, Guangdong, China Abstract 1. The efflux pump p-glycoprotein (P-gp/ABCB1) has received enormous attention in drug (xenobiotic) disposition due to its role in modulation of the drug availability and in protection of sensitive organs. 2. P-gp mediated efflux is one of main mechanisms for multidrug resistance in cancer cells. A main approach to reverse the resistance and restore the drug efficacy is to use specific inhibitors of P-gp that suppress the efflux activity. 3. This review summarizes the binding capabilities of known chemical inhibitors based on the analyses of structure–activity relationships, and computational modeling of the inhibitors as well as the binding site of P-gp protein. 4. The molecular models will facilitate the design of lead inhibitors as drug candidates. Also, it helps scientists in early drug discovery phase to synthesize chemical series with better understanding of their P-gp binding liabilities. Keywords Drug discovery, P-glycoprotein, SAR, structure transport relationships, transporters History Received 6 February 2013 Revised 24 March 2013 Accepted 26 March 2013 Published online 25 April 2013 Introduction P-glycoprotein (P-gp/ABCB1) is a well-known efflux pump that confers multidrug resistance to cancer cells, causing significant failures in cancer treatment (Ling et al., 1983; Longley & Johnston, 2005; Sharom, 2011). The P-gp pump is a 170 kDa protein which like other members of the ABC transporters is organized into two transmembrane regions, each containing six membrane spanning a-helices (trans- membrane domains (TMDs)), and two nucleotide binding domains (NBDs) (Figure 1; Schinkel, 1999). P-gp has an important role in the absorption, distribution, metabolism and elimination (ADME; pharmacokinetics) of various types of drugs (Fromm, 2000; Kim et al., 1998; Ste ˛pien ´ et al., 2012). The interplay between the drug transport by P-gp and metabolism is well characterized and its effects on drug bioavailability and hepatic disposition have been recognized (Benet, 2009; Salphati, 2009). P-gp is expressed primarily at many physiological barriers, including the intestinal epithelium, hepatocytes, renal prox- imal tubular cells, the adrenal gland and the blood brain barrier (Sharom, 2008). This is consistent with its role in limiting absorption, facilitating elimination of xenobiotics, and in protecting sensitive CNS organs from potential toxins. The substrate specificity for P-gp is very broad. Compounds ranging from a molecular weight of 250 to 4000 Da are known to be transported by P-gp (Lam et al., 2001; Ramachandra et al., 1998). Understanding of this substrate promiscuity has been aided by the crystal structure for mouse P-gp, which reveals a large binding cavity allowing for simultaneous binding of two substrate molecules (Aller et al., 2009; Loo et al., 2003) (Figure 1). To date, the structural features associated with P-gp substrates and non- substrates remain elusive. However, most P-gp substrates are hydrophobic and partition into the lipid bilayer (Gatlik- Landwojtowicz et al., 2006). For this reason, P-gp has been likened to a molecular ‘‘hydrophobic vacuum cleaner’’ (Aller et al., 2009; Raviv et al., 1990). Although the mechanisms for transport of substrates by P-gp are still under debate, it is a consensus that two protein conformations are required for substrate binding and release, respectively (Lee et al., 2008; Locher, 2009; Oldham et al., 2008; Rosenberg et al., 2001, 2003; Sauna & Ambudkar, 2007; Tombline et al., 2005). Identifying the substrates and inhibitors of P-pg assumes great importance in clinical pharmacology particularly in prediction of drug–drug interactions (Chang et al., 2006). Moreover, the specific inhibitors of P-gp can be applied to reverse the multidrug resistance and restore the anticancer effects by suppressing the drug-efflux ability. Scientists have been searching the structural rules making P-gp substrates/ inhibitors for decades. The simple rules of P-gp substrates have been formulated that relate to the number and the positions of hydrogen-bond acceptors (Hochman et al., 2006; Seelig & Landwojtowicz, 2000). Theoretical models of P-gp substrates and inhibitors using sophisticated statistical approaches have been widely constructed (Dolghih et al., Address for correspondence: Baojian Wu, PhD, Division of Pharmaceutics, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, Guangdong 510632, China. E-mail: bj.wu@hotmail.com *These authors contributed equally to this paper. Xenobiotica Downloaded from informahealthcare.com by University of Notre Dame Australia on 04/30/13 For personal use only.