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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Determination of Hybrid TSPO Ligands with Minimal Impact of SNP (rs6971) through Molecular Docking and MD Simulation Study

Author(s): Anupriya Adhikari*, Anwesh Pandey, Devesh Kumar and Anjani K. Tiwari*

Volume 19, Issue 6, 2022

Published on: 13 April, 2021

Page: [549 - 563] Pages: 15

DOI: 10.2174/1570180818666210413130326

Price: $65


Background: In an endeavor to ascertain high-affinity TSPO ligands with minimal single nucleotide polymorphism (SNP), six hybrid molecules have been identified as new leads for future inflammation PET imaging.

Objective: Genesis for chemical design was encouraged from structural families of well-known ligands FEBMP and PBR28/ DAA1106 that have demonstrated remarkable TSPO binding characteristics.

Methods: All proposed hybrid ligands 1-6 are subjected to molecular docking and simulation studies with wild and mutant protein to study their interactions, binding, consistency of active conformations and are correlated with well-established TSPO ligands.

Results: Each hybrid ligand demonstrate better docking score > -11.00 kcal/mol with TSPO with respect to gold standard PK11195, i.e., -11.00 kcal/mol for 4UC3 and -12.94 kcal/mol for 4UC1. On comparison with FEBMP and GE-180 ({-12.57, -7.24 kcal/mol} for 4UC3 and {-14.10, -11.32 kcal/mol} for 4UC1), ligand 3 demonstrates maximum docking energy (> -15.50 kcal/mol) with minimum SNP (0.26 kcal/mol).

Discussion: Presence of strong hydrogen bond Arg148-3.27Å (4UC1) and Trp50-2.43Å, Asp28- 2.57Å (4UC3) apart from short-range interactions, including π–π interactions with the aromatic residues, such as (Trp39, Phe46, Trp135) and (Trp39, Trp108), attributes towards its strong binding.

Conclusion: Utilizing the results of binding energy, we concluded stable complex formation of these hybrid ligands that could bind to TSPO with the least effect of SNP with similar interactions to known ligands. Overall, ligand 3 stands out as the best ligand having insignificant deviations per residue of protein that can be further explored and assessed in detail for future inflammation PET application after subsequent detailed biological evaluation.

Keywords: TSPO, PET, docking, molecular simulation, rs6971, hybrid ligands.

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