Identification of potential inhibitors against pathogenic missense mutations of PMM2 using a structure-based virtual screening approach

Abstract

The autosomal recessive phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is characterized by defective functioning of the PMM2 enzyme, which is necessary for the conversion of mannose-6-phosphate into mannose-1-phosphate. Here, a computational pipeline was drawn to identify the most significant mutations, and further, we used a virtual screening approach to identify a new lead compound to treat the identified significant mutations. We searched for missense mutation data related to PMM2-CDG in HGMD®, UniProt, and ClinVar. Our search yielded a total of 103 mutations, of which 91 are missense mutations. The D65Y, I132N, I132T, and F183S mutations were classified as deleterious, destabilizing, and altering the biophysical properties using the PredictSNP, iStable, and Align GVGD in silico prediction tools. Additionally, we applied a multistep protocol to screen for an alternative lead compound to the existing CID2876053 (1-(3-chlorophenyl)-3,3-bis(pyridine-2-yl)urea) with affinity to these identified significant mutants. Two compounds, CHEMBL1491007 (6-chloro-4-phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)-1H-quinolin-2-one) and CHEMBL3653029 (5-chloro-4-[6-[(3-fluorophenyl)methylamino]pyridin-2-yl]-N-(piperidin-4-ylmethyl)pyridin-2-amine), exhibited the highest binding affinity with the selected mutants and were chosen for further analysis. Through molecular docking, molecular dynamics simulation, and MMPBSA analysis, we found that the known compound, i.e. CID2876053, has stronger interaction with the D65Y mutant. The newly identified lead compound CHEMBL1491007 showed stronger interaction with the I132N and I132T mutants, whereas the most deleterious mutant, F183S, showed stronger interaction with CHEMBL3653029. This study is expected to aid in the field of precision medicine, and further to in vivo and in vitro analysis of these lead compounds might shed light on the treatment of PMM2-CDG.

Communicated by Ramaswamy H. Sarma

Keywords:

• PMM2-CDG
• variant classification
• virtual screening
• molecular dynamics
• MMPBSA

Acknowledgements

The authors thank the VIT management and BRAF @ CDAC for their encouragement and the provision of facilities.

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors’ contributions

TKD, NJ, and UK were involved in the research design and the acquisition, analysis, and interpretation of the data. TKD, NJ, HZ, and GPDC were involved in the interpretation of the data and in drafting the manuscript. GPDC and HZ supervised the entire study and were involved the research design, the acquisition, analysis, and interpretation of the data, and the drafting of the manuscript. The manuscript was reviewed and approved by all the authors.

Ethics approval and consent to participate

Not applicable.

Competing interests

All authors declare no competing interests.