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Published on: May 9, 2025
Molecular docking studies and in vitro screening of new dihydropyridine derivatives as human MRP1 inhibitors
Kalam Sirisha1, Maddela Chandra Shekhar, Kulandaivelu Umasankar
1Medicinal Chemistry Research Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Andhra Pradesh, India.
Abstract:
The overexpression of multidrug resistance protein 1 (MRP1) by tumor cells results in multidrug resistance (MDR) to structurally unrelated anticancer drugs. Circumvention of MDR by combination of chemosensitizers with antitumor compounds is a new field of investigation in cancer chemotherapy. Much effort has been put-in recently to identify the modulators/inhibitors of MRP1 to overcome the MDR. 1,4-Dihydropyridine (DHP) derivatives are indicated to be a new class of MRP1 inhibitors in cancer treatment. Molecular docking studies were carried out on 48 newly synthesized DHP derivatives with the crystal structure of MRP1 to gain some structural insights on the binding mode and possible interactions with the active site of MRP1 (NBD1). The 10 top-ranked molecules were selectively evaluated, experimentally for their MRP1 inhibitory effect using the insect cell membrane MRP1 ATPase assay. The inhibitory capacity (IC(50) concentrations) of the test compounds was compared with the reported IC(50)- or the K(i)-concentrations for benzbromarone, a standard MRP1 inhibitor. Amongst the compounds tested, compounds IA(1) and IIA(5) were found to exhibit a potent MRP1 inhibitory action with IC(50) values of 20±4 and 14±2 μM (mean±SD), respectively as compared to benzbromarone (IC(50)=4 μM). The compound IIA(5), in particular was found to be more potent than IA(1) in accordance with the docking results. These new DHP derivatives possess promising characteristics for their development as MDR reversal agents.
Insights
New 1,4-dihydropyridine (DHP) derivatives show promise as multidrug resistance (MDR) reversal agents by inhibiting the multidrug resistance protein 1 (MRP1). Compounds IA(1) and IIA(5) demonstrated potent MRP1 inhibition, suggesting potential in overcoming cancer chemotherapy resistance.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cancer Research
Background:
- Multidrug resistance protein 1 (MRP1) overexpression in tumors causes resistance to anticancer drugs.
- Overcoming multidrug resistance (MDR) is crucial for effective cancer chemotherapy.
- Identifying novel MRP1 inhibitors is a key strategy to circumvent MDR.
Purpose of the Study:
- To investigate novel 1,4-dihydropyridine (DHP) derivatives as potential MRP1 inhibitors.
- To explore the binding interactions of DHP derivatives with MRP1 using molecular docking.
- To experimentally validate the MRP1 inhibitory activity of promising DHP candidates.
Main Methods:
- Synthesis of 48 novel 1,4-dihydropyridine (DHP) derivatives.
- Molecular docking studies of DHP derivatives against the MRP1 crystal structure (NBD1).
- Experimental evaluation of MRP1 inhibitory effects using the insect cell membrane MRP1 ATPase assay.
Main Results:
- Molecular docking provided insights into the binding modes of DHP derivatives within the MRP1 active site.
- Compounds IA(1) and IIA(5) exhibited significant MRP1 inhibitory activity with IC(50) values of 20±4 μM and 14±2 μM, respectively.
- Compound IIA(5) showed greater potency than IA(1), aligning with docking predictions, and was compared to benzbromarone (IC(50)=4 μM).
Conclusions:
- The novel DHP derivatives demonstrate potent MRP1 inhibitory activity.
- These compounds show potential as effective agents for reversing multidrug resistance in cancer.
- Further development of these DHP derivatives could lead to improved cancer treatment strategies.
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