title: Rational design of small-molecule stabilizers of spermine synthase dimer by virtual screening and free energy-based approach.
abstract: Snyder-Robinson Syndrome (SRS) is a rare mental retardation disorder which is caused by the malfunctioning of an enzyme, the spermine synthase (SMS), which functions as a homo-dimer. The malfunctioning of SMS in SRS patients is associated with several identified missense mutations that occur away from the active site. This investigation deals with a particular SRS-causing mutation, the G56S mutation, which was shown computationally and experimentally to destabilize the SMS homo-dimer and thus to abolish SMS enzymatic activity. As a proof-of-concept, we explore the possibility to restore the enzymatic activity of the malfunctioning SMS mutant G56S by stabilizing the dimer through small molecule binding at the mutant homo-dimer interface. For this purpose, we designed an in silico protocol that couples virtual screening and a free binding energy-based approach to identify potential small-molecule binders on the destabilized G56S dimer, with the goal to stabilize it and thus to increase SMS G56S mutant activity. The protocol resulted in extensive list of plausible stabilizers, among which we selected and tested 51 compounds experimentally for their capability to increase SMS G56S mutant enzymatic activity. In silico analysis of the experimentally identified stabilizers suggested five distinctive chemical scaffolds. This investigation suggests that druggable pockets exist in the vicinity of the mutation sites at protein-protein interfaces which can be used to alter the disease-causing effects by small molecule binding. The identified chemical scaffolds are drug-like and can serve as original starting points for development of lead molecules to further rescue the disease-causing effects of the Snyder-Robinson syndrome for which no efficient treatment exists up to now.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques In Silico, Inserm UMR-S 973, Paris, France; INSERM, U973, Paris, France; Computational Biophysics and Bioinformatics, Department of Physics and Astronomy, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques In Silico, Inserm UMR-S 973, Paris, France; INSERM, U973, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Martiny
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques In Silico, Inserm UMR-S 973, Paris, France; INSERM, U973, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Lagorce
authors.affiliation: Faculty of Pharmaceutical Sciences, Josai University, Togane, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ikeguchi
authors.affiliation: Computational Biophysics and Bioinformatics, Department of Physics and Astronomy, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Emil
authors.initials: E
authors.lastname: Alexov
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques In Silico, Inserm UMR-S 973, Paris, France; INSERM, U973, Paris, France.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Miteva
mesh_terms: D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D006801:Humans; D008607:Intellectual Disability / Q000188:drug therapy / Q000235:genetics*; D038901:X-Linked Intellectual Disability / Q000188:drug therapy / Q000235:genetics*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D020125:Mutation, Missense; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D013097:Spermine Synthase / Q000737:chemistry* / Q000235:genetics*; D013816:Thermodynamics
chemical_list: D013097:Spermine Synthase