ISSN print edition: 0366-6352
ISSN electronic edition: 1336-9075
Registr. No.: MK SR 9/7

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Homology modelling, vHTS, pharmacophore, molecular docking and molecular dynamics studies for the identification of natural compound-derived inhibitor of MRP3 in acute leukaemia treatment

Femi Olawale, Opeyemi Iwaloye, Kolawole Olofinsan, Oludare M. Ogunyemi, Gideon A. Gyebi, and Ibrahim M. Ibrahim

Nano-Gene and Drug Delivery Group, Department of Biochemistry, School of Life Science, University of Kwazulu Natal, Durban, South Africa



Received: 8 December 2021  Accepted: 9 February 2022


The pivotal role of MRP3 protein in acute leukaemia and the efficacy of natural compounds in cancer treatment have necessitated the current study to identify novel MRP3 inhibitors from natural source. The MRP3 protein was modelled and validated using well-accepted metrics, after which a validated multiple-ligand pharmacophore model (AHHHR_4) was built to screen natural compounds (n = 47,964). The combined pharmacophore screening with molecular docking was conducted to identify the hits drug-like compounds using ADMET profiling. The electronic behaviour of this set of compounds in gas phase was examined using density functional theory. Among the compounds (n = 7) with clean ADMET profile, NPC5486, which possessed the highest binding affinity with MRP3, was further subjected to 50 ns molecular dynamics (MD) simulation to understand its dynamics of binding. Analysis from the resulting MD simulation trajectories of NPC5486 in complex with the model protein alongside that of standard inhibitor (vincristine) showed not only the flexibility and interaction potential of the residues of the MRP3 with NPC5486 as indicated by the RMSF but also stability of the complex as indicated by the RMSD, RoG and number of hydrogen bonds of the ligand–protein complexes. Cluster analysis of the MD simulation trajectory files and dynamics-based MMGBSA computations further revealed that the observed interactions with important residues as well as the free energy contribution per residue were preserved in the dynamic environment. Overall, the current study has revealed drug-like compounds which can serve as potential inhibitors of MRP3 in the treatment of acute leukaemia.

Keywords: Multidrug-resistant protein3 inhibitor; Virtual screening; Homology modelling; Pharmacophore modelling; Density functional theory; Molecular dynamics simulation

Full paper is available at

DOI: 10.1007/s11696-022-02128-w


Chemical Papers 76 (6) 3729–3757 (2022)

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