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In Silico Study in MPO and Molecular Docking of the Synthetic Drynaran Analogues Against the Chronic Tinnitus: Modulation of the M1 Muscarinic Acetylcholine Receptor

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Abstract

Tinnitus is a syndrome that affects the human auditory system and is characterized by a perception of sounds in the absence of acoustic stimuli, or in total silence. Research indicates that muscarinic acetylcholine receptors (mAChRs), especially the M1 type, have a fundamental role in the alterations of auditory perceptions of tinnitus. Here, a series of computer-aided tools were used, from molecular surface analysis software to services available on the web for estimating pharmacokinetics and pharmacodynamics. The results infer that the low lipophilicity ligands, that is, the 1a–d alkyl furans, present the best pharmacokinetic profile, as compounds with an optimal alignment between permeability and clearance. However, only ligands 1a and 1b have properties that are safe for the central nervous system, the site of cholinergic modulation. These ligands showed similarity with compounds deposited in the European Molecular Biology Laboratory chemical (ChEMBL) database acting on the mAChRs M1 type, the target selected for the molecular docking test. The simulations suggest that the 1 g ligand can form the ligand-receptor complex with the best affinity energy order and that, together with the 1b ligand, they are competitive agonists in relation to the antagonist Tiotropium, in addition to acting in synergism with the drug Bromazepam in the treatment of chronic tinnitus.

Graphical Abstract

Description The study of the biological activities of Drynaria bonii led to the ADMET model to be used, mainly in relation to intestinal absorption and brain activity. The web-services made it possible, through a similarity test, to select the M1 muscarinic receptor, used in the ligand-receptor interaction tests, estimating the way of treating tinnitus.

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Data availability

All the data generated or analyzed during this study are included in this published article.

Abbreviations

ADMET:

: Absorption, distribution, metabolism, excretion and toxicity

AMES:

: Ames mutagenicity

BBB:

: Blood–brain barrier

BZP:

: Bromazepam

ChEMBL:

: European molecular biology laboratory

ChRs:

: Cholinergic receptors

CLint,u:

: Intrinsic clearance of the unbound fraction in liver

CNS:

: Central nervous system

CYP450:

: Cytochrome P450

F30% :

: Fraction of bioavailability > 30%

FM:

: Fathead minnow

GPCR:

: G protein-coupled receptor

HBD:

: H-bond donors

H-HT:

: Human hepatotoxicity

HIA:

: Human intestinal absorption

LC50 :

: Lethal concentration

LD50 :

: Lethal dose

logD:

: Buffer lipophilicity

logP:

: Intrinsic lipophilicity

L-R:

: Ligand-receptor

mAChRs:

: Muscarinic acetylcholine receptors

MDCK:

: Madin-darby canine kidney

MPO:

: Multiparameter optimization

MTD:

: Maximum tolerated dose

MW:

: Molecular weight

NMA:

: Normal mode analysis

Papp :

: Passive permeability

P-gp:

: P-glycoprotein

RMSD:

: Root mean square deviation

TPSA:

: Topological polar surface area

TTP:

: Tiotropium

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Authors and Affiliations

  1. Graduate Program in Natural Sciences, Center for Science and Technology, State University of Ceará, Fortaleza, CE, Brazil

    Matheus Nunes da Rocha & Emmanuel Silva Marinho

  2. Institute of Engineering and Sustainable Development, Academic Master in Sociobiodiversity and Sustainable Technologies, University of International Integration of Afro-Brazilian Lusofonia, Acarape, CE, Brazil

    Aluísio Marques da Fonseca

  3. Group of Theoretical Chemistry and Electrochemistry, State University of Ceará, Limoeiro Do Norte, CE, Brazil

    Adriana Nogueira Machado Dantas, Emmanuel Silva Marinho & Gabrielle Silva Marinho

  4. Chemistry Department, Regional University of Cariri, Crato, CE, Brazil

    Hélcio Silva dos Santos

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Conceptualization, MNR and ANMD; supervision, ESM and HSS; writing—original draft preparation, MNR, GSM and HSS; reviewing and editing of the manuscript, ESM, ANMD and AMF; all authors read and agreed to the fnal version of the manuscript.

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da Rocha, M.N., da Fonseca, A.M., Dantas, A.N.M. et al. In Silico Study in MPO and Molecular Docking of the Synthetic Drynaran Analogues Against the Chronic Tinnitus: Modulation of the M1 Muscarinic Acetylcholine Receptor. Mol Biotechnol 66, 254–269 (2024). https://doi.org/10.1007/s12033-023-00748-5

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