Computational algorithmic and molecular dynamics study of functional and structural impacts of non-synonymous single nucleotide polymorphisms in human DHFR gene |
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| Institution: | 1. Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh;2. Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh;3. Institute for Glycomics, Griffith University, Parklands Dr. Southport, QLD 4222, Australia;4. School of Pharmacy, Monash University Malaysia, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;1. Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China;2. Cancer Center of Nanjing Medical University, Department of Molecular and Genetic Toxicology, Nanjing Medical University, Nanjing, China;1. Department of Bioinformatics, SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat, 131 029, Haryana, India;2. Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, Banaras Hindu University, Varanasi, 221 005, Uttar Pradesh, India;3. Medical Biotechnology Division, Department of Biochemistry, Pt. Jawaharlal Nehru Memorial Medical College, Raipur, 492 001, Chhattisgarh, India;1. Molecular Modeling and Drug Design Laboratory, Pharmacology Research Division, Bangladesh Council of Scientific and Industrial Research, Chittagong, 4220, Bangladesh;2. Department of Biochemistry and Biotechnology, University of Science & Technology Chittagong, Chittagong, 4202, Bangladesh;3. Department of Pharmacy, University of Chittagong, Chittagong, 4331, Bangladesh |
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| Abstract: | Human dihydrofolate reductase (DHFR) is a conserved enzyme that is central to folate metabolism and is widely targeted in pathogenic diseases as well as cancers. Although studies have reported the fact that genetic mutations in DHFR leads to a rare autosomal recessive inborn error of folate metabolism and drug resistance, there is a lack of an extensive study on how the deleterious non-synonymous SNPs (nsSNPs) disrupt its phenotypic effects. In this study, we aim at discovering the structural and functional consequences of nsSNPs in DHFR by employing a combined computational approach consisting of ten recently developed in silico tools for identification of damaging nsSNPs and molecular dynamics (MD) simulation for getting deeper insights into the magnitudes of damaging effects. Our study revealed the presence of 12 most deleterious nsSNPs affecting the native phenotypic effects, with three (R71T, G118D, Y122D) identified in the co-factor and ligand binding active sites. MD simulations also suggested that these three SNPs particularly Y122D, alter the overall structural flexibility and dynamics of the native DHFR protein which can provide more understandings into the crucial roles of these mutants in influencing the loss of DHFR function. |
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| Keywords: | nsSNPs DHFR folate molecular dynamics simulations cancer |
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