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Identification of potential inhibitors against pathogenic missense mutations of PMM2 using a structure-based virtual
D Thirumal Kumar1, Nikita Jain1, S Udhaya Kumar1
1School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, India.
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.
Insights
Computational methods identified key mutations in phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG). New lead compounds were screened to potentially treat these PMM2-CDG mutations.
Area of Science:
- Biochemistry
- Computational Biology
- Genetics
Background:
- Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) results from defective PMM2 enzyme function.
- The PMM2 enzyme is crucial for converting mannose-6-phosphate to mannose-1-phosphate.
Purpose of the Study:
- To computationally identify significant PMM2 mutations.
- To virtually screen for novel lead compounds to treat identified PMM2 mutations.
Main Methods:
- Searched mutation databases (HGMD®, UniProt, ClinVar) for PMM2-CDG missense mutations.
- Utilized in silico tools (PredictSNP, iStable, Align GVGD) to classify mutation significance.
- Applied virtual screening, molecular docking, molecular dynamics, and MMPBSA analysis to evaluate lead compounds.
Main Results:
- Identified 103 mutations, with 91 being missense; D65Y, I132N, I132T, and F183S were classified as deleterious.
- Screened compounds CHEMBL1491007 and CHEMBL3653029 showed high binding affinity.
- CID2876053 interacted strongly with D65Y; CHEMBL1491007 with I132N/I132T; CHEMBL3653029 with F183S.
Conclusions:
- This study provides a computational approach to identify significant PMM2-CDG mutations and potential therapeutic compounds.
- The identified lead compounds, CHEMBL1491007 and CHEMBL3653029, warrant further in vitro and in vivo investigation for PMM2-CDG treatment.
- Findings contribute to the advancement of precision medicine for PMM2-CDG.
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