Beyond Mutation Diversity: Common Pathogenic Mechanism for Putative Intervention Sites in Monogenic Diseases
- 1Department of Physics and Astronomy, College of Science, Clemson University, Clemson, SC 29634, USA
- 2Medical Biophysics Graduate Program, College of Science, Clemson University, Clemson, SC 29634, USA
- 3Institute for Human Genetics, Clemson University, Greenwood, SC 29646, USA
Abstract
Monogenic disorders present a compelling target for drug discovery due to their clear, single-gene etiology. Yet, effective therapies remain scarce, largely because diverse mutation types scattered across a protein obstruct targeted drug design. In this study, we leverage MOGEDO, a curated database of monogenic disorders, to test whether different pathogenic genotypes within a single protein converge on a common molecular mechanism. By clustering MOGEDO proteins into eight functional families and analyzing representative proteins carrying both benign and pathogenic mutations, we integrated molecular dynamics, network analysis, and side-chain entropy metrics. Our findings reveal that distinct pathogenic mutations disrupt the structural and dynamic properties of the wild-type and benign protein through common pathways. By demonstrating that diverse disease-causing mutations manifest a unified pathogenic phenotype, this work provides a framework for designing broad-spectrum therapeutics that target common putative intervention sites rather than individual mutations.
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BibTeX
@article{bikash2026beyond,
title = {{Beyond Mutation Diversity: Common Pathogenic Mechanism for Putative Intervention Sites in Monogenic Diseases}},
author = {Bikash KC and Nirav Modha and Pitambar Poudel and Shailesh Kumar Panday and Emil Alexov},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219432},
url = {https://www.mdpi.com/1422-0067/27/21/9432},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Beyond Mutation Diversity: Common Pathogenic Mechanism for Putative Intervention Sites in Monogenic Diseases
AU - Bikash KC
AU - Nirav Modha
AU - Pitambar Poudel
AU - Shailesh Kumar Panday
AU - Emil Alexov
PY - 2026
DA - 2026/10/22
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219432
UR - https://www.mdpi.com/1422-0067/27/21/9432
AB - Monogenic disorders present a compelling target for drug discovery due to their clear, single-gene etiology. Yet, effective therapies remain scarce, largely because diverse mutation types scattered across a protein obstruct targeted drug design. In this study, we leverage MOGEDO, a curated database of monogenic disorders, to test whether different pathogenic genotypes within a single protein converge on a common molecular mechanism. By clustering MOGEDO proteins into eight functional families and analyzing representative proteins carrying both benign and pathogenic mutations, we integrated molecular dynamics, network analysis, and side-chain entropy metrics. Our findings reveal that distinct pathogenic mutations disrupt the structural and dynamic properties of the wild-type and benign protein through common pathways. By demonstrating that diverse disease-causing mutations manifest a unified pathogenic phenotype, this work provides a framework for designing broad-spectrum therapeutics that target common putative intervention sites rather than individual mutations.
SN - 1422-0067
ER -