Highlights
- •Docking scores revealed the tightest interaction modes for zuclopenthixol-S1PL (ΔGb -7.96 kcal/mol) and lurasidone-CypD (ΔGb -8.84 kcal/mol) complexes.
- •MD simulations proved the appropriate and stable accommodation of top-ranked drugs inside enzyme binding sites during 100 ns.
- •Binding trajectories indicated that hydroxyethyl piperazine of zuclopenthixol and benzisothiazole of lurasidone flipped inside the binding pocket to interact with adjacent polar and apolar residues.
- •Non-polar hydrophobic interactions played significant role in the stability of drug-enzyme complexes.
- •Lurasidone binding pattern confirmed previous reports on X-ray structures of other norbornane maleimide derivatives as CypD inhibitors.
- •Asn144, Phe102 and Phe155 served as dominant residues in providing stable binding pose of lurasidone through both exo and endo conformations.
- •Although practical outputs are yet to be explored, MD results provide structural basis for S1PL and CypD binding events that are difficult to address experimentally.
Abstract
Multiple sclerosis (MS) is an autoimmune neurodegenerative disease affecting numerous
people worldwide. While the relapsing subtypes of MS are to some extent treatable,
the disease remains incurable leading to progressive disability. Limited efficacy
of current small molecule drugs necessitates development of efficient and safe MS
medications. Accordingly, drug repurposing is an invaluable strategy that recognizes
new targets for known drugs especially in the field of poorly addressed therapeutic
areas. Current drug discovery necessitates the identification of potential binding
molecules to the intended biomolecular target(s). In this regard, current study was
devoted to in silico repurposing of 263 small molecule CNS drugs to achieve superior
binders to some MS-related targets. On the basis of molecular docking scores, thioxanthene
and benzisothiazole-based antipsychotics could be identified as potential binders
to MS-related enzymes sphingosine-1-phosphate lyase (S1PL) and cyclophilin D (CypD).
Tightest interaction modes were observed for zuclopenthixol-S1PL (ΔGb -7.96 kcal/mol) and lurasidone-CypD (ΔGb -8.84 kcal/mol) complexes. Molecular dynamics (MD) simulations proved the appropriate
and stable accommodation of top-ranked drugs inside enzyme binding sites during 100
ns. Hydroxyethyl piperazine of zuclopenthixol and benzisothiazole of lurasidone flipped
inside the binding pocket to interact with adjacent polar and apolar residues. Solvent
accessible surface area (SASA) fluctuations confirmed the results of binding trajectory
analysis and showed that non-polar hydrophobic interactions played significant roles
in acquired stabilities. Our results on lurasidone binding pattern were interestingly
in accordance with previous reports on X-ray structures of other norbornane maleimide
derivatives as CypD inhibitors. According to this, Asn144, Phe102 and Phe155 served
as dominant residues in providing stable binding pose of lurasidone through both exo
and endo conformations. Although experimental results are necessary to be achieved,
the outcomes of this study proposed the potentiality of some thioxanthene and benzisothiazole-based
antipsychotics for binding to S1PL and CypD, respectively as MS-related targets.
Keywords
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Article info
Publication history
Accepted:
March 14,
2023
Received in revised form:
February 10,
2023
Received:
March 28,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier B.V. All rights reserved.
