Molecular modeling, dynamics, and an insight into the structural inhibition of cofactor independent phosphoglycerate mutase isoform 1 from Wuchereria bancrofti using cheminformatics and mutational studies

Abstract

Phosphoglycerate mutase catalyzes the interconversion between 2-phosphoglycerate and 3-phosphoglycerate in the glycolytic and gluconeogenic pathways. They exist in two unrelated forms, that is either cofactor (2,3-diphosphoglycerate) dependent or cofactor-independent. These two enzymes have no similarity in amino acid sequence, tertiary structure, and in catalytic mechanism. Wuchereria bancrofti (WB) contains the cofactor-independent form, whereas other organisms can possess the dependent form or both. Since, independent phosphoglycerate mutase (iPGM) is an essential gene for the survival of nematodes, and it has no sequence or structural similarity to the cofactor-dependent phosphoglycerate mutase found in mammals, it represents an attractive drug target for the filarial nematodes. In this current study, a putative cofactor-iPGM gene was identified in the protein sequence of the WB. In the absence of crystal structure, a three-dimensional structure was determined using the homology modeling approximation, and the most stable protein conformation was identified through the molecular dynamics simulation studies, using GROMACS 4.5. Further, the functional or characteristic residues were identified through the sequence analysis, potential inhibitors were short-listed and validated, and potential inhibitors were ranked using the cheminformatics and molecular dynamics simulations studies, Prime MM-GBSA approach, respectively.

Keywords:

• molecular modeling
• molecular dynamics simulation
• molecular docking
• virtual screening
• phosphoglycerate mutase
• MM-GBSA

Acknowledgment

Om Prakash Sharma is grateful to Council of Scientific & Industrial Research (CSIR), India for the Senior Research Fellowship (SRF). Research carried on at the laboratory of the Centre for Excellence in Bioinformatics, Pondicherry University, India is funded by the Department of Information Technology (DIT) and the Department of Biotechnology (DBT), Government of India, New Delhi, India. Birgit Strodel gratefully acknowledges the Julich Supercomputing centre, Germany for providing and maintaining the computing resources used in this work.