Molecular Modelling of Human Multidrug Resistance Protein 5 (ABCC5)

Abstract

Multidrug resistance protein 5 (MRP5/ABCC5) is a 161 kDa member of the super family of ATPbinding cassette (ABC) superfamily of transmembrane transporters that is clinically relevant for its ability to confer multidrug resistance by actively effluxing anticancer drugs. ABCC5 has also been identified as an efflux transporter of cGMP (cyclic guanosine monophosphate). Elevated intracellular levels of cGMP in cancer cells have been implicated in several clinical studies, that may induce apoptosis, and as a result many different cancer cells seem to overcome this deleterious effect by increased efflux of cGMP through ABCC5. Thus inhibition of ABCC5 may have cytotoxic effects mediated through cGMP and it will also increase the intracellular concentration of other drugs that are aimed for the treatment of cancer which are otherwise exported out of the cells. Considering the functional importance and lack of X-ray crystal structure of ABCC5, present work was undertaken to construct 3D structure of protein using homology modeling protocol of YASARA structure (V. 16.3.28). In this study, five different ABC templates (PDB ID's: 4F4C, 4Q9H, 4M1M, 4M2T and 4KSD) were used for homology modeling. Five models were constructed on each template and a hybrid model was built using all five templates. All models were refined and ranked as per their overall Z-score. The top ranked ABBC5 model was based on template 4Q9H that had 91.2% of residues in allowed regions as revealed by PROCHECK-NMR and the QMEAN score was 0.54 which indicated a reliable model. The results of the study and the proposed model can be further used for elucidating the structural and functional aspects of ABCC5 and to gain more insights to the molecular basis of ABCC5 inhibition through docking studies.

Rigorous sampling of docking poses unveils binding hypothesis for the halogenated ligands of L-type Amino acid Transporter 1 (LAT1)

“…As such, it seems reasonable to investigate the transporter-ligand interactions using a homology model. The models were constructed using MODELLER as described previously 38 and were assessed on the basis of normalized Discrete Optimized Protein Energy (DOPE) score 55,56 . The top-ranked model in terms of the DOPE score (−0.41) was analyzed by means of residue hydrophobicity, and electrostatic potential calculations (see Supplementary Information, Figs S1, S2).…”

Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular α1+/β3- Interface of the GABAA Receptor by Molecular Modeling

“…We used the previously reported sequence alignment for building the models ( Puthenkalam et al, 2016 ). The top-scoring model, with respect to the DOPE score ( Shen and Sali, 2006 ; Singh, 2016 , p. 5), was selected for the docking studies. The model was subjected to automated structure preparation using the Protein Preparation Wizard ( Schrodinger Suite 2015, 2015 ) in the Schrödinger Suite in order to optimize the hydrogen bonding network, and enable proper protonation of titratable residues and optimal selection of the Asn, Gln, and His side-chain orientation.…”