Abstract
Background: Based on the sequences of their catalytic domains, the astacins can be grouped into several major subfamilies such as digestive and hatching enzymes, meprin cluster and BMP1/ Tolloid like Proteases (BTP). Ethylene Diamine Tetra-Acetate (EDTA) was used to dock into the active site cleft of the astacins to know the interaction network and to identify the important residues for binding.
Introduction: Comparative analysis of the binding interactions helps to reveal the binding affinity of the ligand to the astacins. Virtual alanine screening helps to identify the hotspot residues on the protease which act as potential contributors to protein-ligand stability. Pharmacophore analysis generates common features among all three clusters of the astacin family which helps in significant interactions between the astacins and EDTA.
Methods: Comparative homology modeling and docking study were performed by MODELLER 9.10 and LibDock respectively. To know the importance of interacting residues, in silico alanine scanning was done. Pharmacophore modeling was elaborated by using the information obtained from receptorligand complexes.
Results: Homology model explained the structure and function of the unknown astacins. It was observed that several interactions such as hydrogen bonding, pi-sigma, electrostatic and van der Waal’s were involved in EDTA binding. The important pharmacophoric features such as hydrogen bond acceptor, positive ionisable and negative ionisable are involved in significant interactions between astacins and EDTA.
Conclusion: Understanding the inhibitor selectivity of astacins via the contribution of specific residues could help in the design of better therapeutics targeting astacins with high binding affinity.
Keywords: Astacins, homology modeling, docking, virtual alanine scanning, hotspot residues, receptor-ligand pharmacophore.
Graphical Abstract
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