Structure prediction and discovery of inhibitors against phosphopantothenoyl cysteine synthetase of Acinetobacter baumannii

Abstract

Acinetobacter baumannii is an extremely dangerous multidrug-resistant (MDR) gram-negative pathogen which poses a serious life-threatening risk in immunocompromised patients. Phosphopantothenoyl cysteine synthetase (PPCS) catalyzes the formation of an amide bond between L-cysteine and phosphopantothenic acid (PPA) to form 4′- Phosphopantothenoylcysteine during Coenzyme A (CoA) biosynthesis. CoA is a crucial cofactor for cellular survival and inhibiting its synthesis will result in cell death. Bacterial PPCS differs from eukaryotic PPCS in a number of ways like it exists as a C-terminal domain of a PPCDC/PPCS fusion protein whereas eukaryotic PPCS exists as an independent protein. This difference makes it an attractive drug target. For which a conventional iterative approach of SBDD (structure-based drug design) was used, which began with three-dimensional structure prediction of AbPPCS using PHYRE 2.0. A database of FDA-approved compounds (Drug Bank) was then screened against the target of interest by means of docking score and glide energy, leading to the identification of 6 prominent drug candidates. The shortlisted 6 molecules were further subjected to all-atom MD simulation studies in explicit-solvent conditions (using AMBER force field). The MD simulation studies revealed that the ligands DB65103, DB449108 and DB443210, maintained several H-bonds with intense van der Waals contacts at the active site of the protein with high binding free energies: −11.42 kcal/mol, −10.49 kcal/mol and −10.98 kcal/mol, respectively, calculated via MM-PBSA method. Overall, binding of these compounds at the active site was found to be the most stable and robust highlighting the potential of these compounds to serve as antibacterials.

Communicated by Ramaswamy H. Sarma

Keywords:

• Drug repurposing
• virtual screening
• MD simulation
• docking
• antibiotics
• Coenzyme A

Acknowledgements

Dr. Pradeep Sharma and Dr. Sujata Sharma thank Indian Council of Medical Research, ICMR for extramural grant. Dr. Akshita Gupta thanks Indian Council of Medical Research, ICMR for fellowship. Dr. Viswanathan V thanks Department of Science and Technology (DST), SERB for National Postdoctoral Fellowship. Dr T. P. Singh thanks Department of Science and Technology (DST) for SERB Distinguished Research Professorship. The Supercomputing Facility for Bioinformatics & Computational Biology (SCFBio), IIT Delhi, is gratefully acknowledged for providing computational support.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethical standards

Ethical standards are compulsory for studies relating to human and animal subjects.

Additional information

Funding

Dr. Pradeep Sharma and Dr. Sujata Sharma thank Indian Council of Medical Research, ICMR for extramural grant. Dr. Akshita Gupta thanks Indian Council of Medical Research, ICMR for fellowship. Dr. Viswanathan V thanks Department of Science and Technology (DST), SERB for National Postdoctoral Fellowship. Dr T. P. Singh thanks Department of Science and Technology (DST) for SERB Distinguished Research Professorship. The Supercomputing Facility for Bioinformatics & Computational Biology (SCFBio), IIT Delhi, is gratefully acknowledged for providing computational support.