title: Molecular basis for the affinity and specificity in the binding of five-membered iminocyclitols with glycosidases: an experimental and theoretical synergy.
abstract: An unusual substituent dictated complementarity in the inhibition of amino-modified five-membered iminocyclitols toward various glycosidases was reported by us. These intriguing results encouraged us to seek a molecular level explanation for the observation that may facilitate the design of specific iminocyclitol inhibitors against glycosidases of choice. We present here a detailed theoretical account that is substantiated with some new experimental investigations on the molecular origins of the differential affinities of iminocyclitols with various glycosidases. The studies involve docking/scoring, molecular dynamics simulations followed by syntheses of a few novel five-membered iminocyclitols and their in vitro binding assays. Directional hydrogen bonds and snug fit of the ligands are implicated as contributory to the observed selectivities. The observed synergy between the computations and experiment is likely to spur further research in the design of novel iminocyclitols with specific inhibitory activities.
authors.affiliation: Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India; Supercomputing Facility for Bioinformatics & Computational Biology, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Shandilya
authors.affiliation: Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India.
authors.forename: Muthupandian
authors.initials: M
authors.lastname: Ganesan
authors.affiliation: Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India.
authors.forename: Firdaus
authors.initials: F
authors.lastname: Parveen
authors.affiliation: Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India. Electronic address: ramesh@chemistry.iitd.ac.in.
authors.forename: Namakkal G
authors.initials: NG
authors.lastname: Ramesh
authors.affiliation: Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India; Supercomputing Facility for Bioinformatics & Computational Biology, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India; Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India. Electronic address: bjayaram@chemistry.iitd.ac.in.
authors.forename: B
authors.initials: B
authors.lastname: Jayaram
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D010880:Piperidines; D006026:Glycoside Hydrolases
keywords: Binding affinity; Chaperone; Glycosidases; Iminocyclitols; Molecular dynamics