Pharmacoinformatic Approaches to Design Natural Product Type Ligands of ABC-Transporters

Klepsch, Freya; Jabeen, Ishrat; Chiba, Peter; Ecker, Gerhard F.

doi:10.2174/138161210791163992

Cited by 18 publications

(17 citation statements)

References 58 publications

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“…Due to the absence of co-crystal structures of human ABCB1, our docking studies were based on homology model of human ABCB1 developed using recently published corrected mouse ABCB1 crystal structure [48]. Motesanib is comprised of required pharmacophoric groups, such as hydrophobic groups and/or aromatic ring centers (3,3-dimethyl-2,3-dihydroindole and pyridine ring), hydrogen-bond acceptors and hydrogen-bond donor groups (pyridine ring nitrogen, indole -NH and carboxamide) that have been described important for interaction with the drug-binding cavity of ABCB1 transporters [59]. Moreover, motesanib is reasonably hydrophobic as evident from calculated logP value of 3.5.…”

Section: Discussionmentioning

confidence: 99%

Motesanib (AMG706), a potent multikinase inhibitor, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1

Wang

Kathawala

Zhang

et al. 2014

Biochemical Pharmacology

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Cancer cells often become resistant to chemotherapy through a phenomenon known as multidrug resistance (MDR). Several factors are responsible for the development of MDR, preeminent among them being the accelerated drug efflux mediated by overexpression of ATP binding cassette (ABC) transporters. Some small molecule tyrosine kinase inhibitors (TKIs) were recently reported to modulate the activity of ABC transporters. Therefore, the purpose of this study was to determine if motesanib, a multikinase inhibitor, could reverse ABCB1-mediated MDR. The results showed that motesanib significantly sensitized both ABCB1-transfected and drug-selected cell lines overexpressing this transporter to its substrate anticancer drugs. Motesanib significantly increased the accumulation of [3H]-paclitaxel in ABCB1 overexpressing cells by blocking the efflux function of ABCB1 transporter. In contrast, no significant change in the expression levels and localization pattern of ABCB1 was observed when ABCB1 overexpressing cells were exposed to 3 µM motesanib for 72 h. Moreover, motesanib stimulated the ATPase activity of ABCB1 in a concentration-dependent manner, indicating a direct interaction with the transporter. Consistent with these findings, the docking studies indicated favorable binding of motesanib within the transmembrane region of homology modeled human ABCB1. Here, we report for the first time, motesanib, at clinically achievable plasma concentrations, antagonizes MDR by inhibiting the efflux activity of the ABCB1 transporter. These findings may be useful for cancer combination therapy with TKIs in the clinic.

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Section: Discussionmentioning

confidence: 99%

Motesanib (AMG706), a potent multikinase inhibitor, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1

Wang

Kathawala

Zhang

et al. 2014

Biochemical Pharmacology

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“…30, 31 Along with that, there have been considerable efforts in predicting and designing Pgp substrates/inhibitors. 32, 33 Using a recently reported prediction method (a support vector machine method available from http://pgp.althotas.com), 33 we tested whether our peptide analogs 1 to 10 are predicted to be Pgp substrates. Interestingly, the results predicted that all ten analogs are potential Pgp substrates.…”

Section: Discussionmentioning

confidence: 99%

Development of Peptide-Based Reversing Agents for P-Glycoprotein-Mediated Resistance to Carfilzomib

Kim

et al. 2012

Mol. Pharmaceutics

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Carfilzomib is a novel class of peptidyl epoxyketone proteasome inhibitor and has demonstrated promising activity in multiple clinical trials to treat patients with multiple myeloma and other types of cancers. Here, we investigated molecular mechanisms underlying acquired resistance to carfilzomib and a potential strategy to restore cellular sensitivity to carfilzomib. H23 and DLD-1 cells (human lung and colon adenocarcinoma cell lines) with acquired resistance to carfilzomib displayed marked cross-resistance to YU-101, a closely related proteasome inhibitor, and paclitaxel, a known substrate of Pgp. However, carfilzomibresistant cells remained sensitive to bortezomib, a clinically used dipeptide with boronic acid pharmacophore. In accordance with these observations, carfilzomib-resistant H23 and DLD-1 cells showed marked upregulation of P-glycoprotein (Pgp) as compared to their parental controls, and coincubation with verapamil, a Pgp inhibitor, led to an almost complete restoration of cellular sensitivity to carfilzomib. These results indicate that Pgp upregulation plays a major role in the development of carfilzomib resistance in these cell lines. In developing a potential strategy to overcome carfilzomib resistance, we as a proof of concept prepared a small library of peptide analogues derived from the peptide backbone of carfilzomib and screened these molecules for their activity to restore carfilzomib sensitivity when cotreated with carfilzomib. We found that compounds as small as dipeptides are sufficient in restoring carfilzomib sensitivity. Taken together, we found that Pgp upregulation plays a major role in the development of resistance to carfilzomib in lung and colon adenocarcinoma cell lines and that small peptide analogues lacking the pharmacophore can be used as agents to reverse acquired carfilzomib resistance. Our findings may provide important information in developing a potential strategy to overcome drug resistance.

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“…Appropriate medicinal chemistry approaches facilitated by well-established in silico techniques, including homology modeling [59], MD simulations [60, 61], virtual screening [62, 63], QSAR [64, 65], and SBDD [66], can and have been used to drive therapeutic discovery for ABC proteins, mainly those requiring functional inactivation (i.e., ABCC1, ABCB1, and ABCG2 as previously mentioned). For example, inhibitors of ABCB1 have been identified using a combination of in silico techniques, and these small molecules are currently being evaluated in vitro as well as in vivo for inhibition of tumorigenesis [67, 68].…”

Section: In Silico Methods Facilitate Drug Discovery For Disease-amentioning

confidence: 99%

“…Additional approaches which have demonstrated usefulness in solving the drug design problem involve QSAR and SBDD. QSAR aims to identify bioactive modulators by evaluating the predicted functional activity of a spectrum of drug derivatives [64, 65], while SBDD uses scaffolds of known modulators to precisely reposition/modify chemical moieties in order to improve predicted binding affinity and thus putative drug efficacy [66]. Importantly, these in silico approaches have been frequently used to the develop small molecule modulators of ABC transporters, mainly ABCB1, with several examples of success [64–66].…”

Section: In Silico Methods Facilitate Drug Discovery For Disease-amentioning

confidence: 99%

Biophysical Approaches Facilitate Computational Drug Discovery for ATP-Binding Cassette Proteins

Molinski

Bozóky

Iram

et al. 2017

International Journal of Medicinal Chemistry

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Although membrane proteins represent most therapeutically relevant drug targets, the availability of atomic resolution structures for this class of proteins has been limited. Structural characterization has been hampered by the biophysical nature of these polytopic transporters, receptors, and channels, and recent innovations to in vitro techniques aim to mitigate these challenges. One such class of membrane proteins, the ATP-binding cassette (ABC) superfamily, are broadly expressed throughout the human body, required for normal physiology and disease-causing when mutated, yet lacks sufficient structural representation in the Protein Data Bank. However, recent improvements to biophysical techniques (e.g., cryo-electron microscopy) have allowed for previously “hard-to-study” ABC proteins to be characterized at high resolution, providing insight into molecular mechanisms-of-action as well as revealing novel druggable sites for therapy design. These new advances provide ample opportunity for computational methods (e.g., virtual screening, molecular dynamics simulations, and structure-based drug design) to catalyze the discovery of novel small molecule therapeutics that can be easily translated from computer to bench and subsequently to the patient's bedside. In this review, we explore the utility of recent advances in biophysical methods coupled with well-established in silico techniques towards drug development for diseases caused by dysfunctional ABC proteins.

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Pharmacoinformatic Approaches to Design Natural Product Type Ligands of ABC-Transporters

Cited by 18 publications

References 58 publications

Motesanib (AMG706), a potent multikinase inhibitor, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1

Motesanib (AMG706), a potent multikinase inhibitor, antagonizes multidrug resistance by inhibiting the efflux activity of the ABCB1

Development of Peptide-Based Reversing Agents for P-Glycoprotein-Mediated Resistance to Carfilzomib

Biophysical Approaches Facilitate Computational Drug Discovery for ATP-Binding Cassette Proteins

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