EHS
EHS

Investigation of [ 3 H]diazepam derivatives as allosteric modulators of GABAA receptor α 1 β 2 γ 2 subtypes: combination of molecular docking/dynamic simulations, pharmacokinetics/drug-likeness prediction, and QSAR analysis



doi: 10.1007/s11224-022-02029-4.


Online ahead of print.

Affiliations

Item in Clipboard

Rachida Djebaili et al.


Struct Chem.


.

Abstract

In this paper, a data set of [3H] diazepam derivatives was analyzed using various computational methods: molecular docking/dynamic simulations, and QSAR analysis. The main aims of these studies are to understand the binding mechanisms by which benzodiazepines allosterically modulate GABAA receptor α1β2γ2 subtypes, from inducing neuronal inhibition at lower doses to the anesthetic effect at higher doses, and also, to define the structural requirements that contribute to improving the response of GABAA1β2γ2 receptor to benzodiazepine drugs. The results of the molecular docking study allowed selecting Ro12-6377 and proflazepam as the best modulators for the four binding sites simultaneously. Subsequently, the stability of the selected complexes was investigated by performing molecular dynamics simulation. The latter confirmed the features of both modulators to exert direct effects on the chloride-channel lining residues. Pharmacokinetics and drug-likeness profile were assessed through in silico tool. Furthermore, a QSAR analysis was conducted using an improved vemolecular dynamics simulations proposed byrsion of PLS regression. The goodness of fit and the predictive power of the resulting PLS model were estimated according to internal and external validation parameters: R 2 = 0.632, R 2adj = 0.584, F = 12.806; p-value = 6.2050e – 07, Q 2loo = 0.639, and Q 2F3 = 0.813. Clearly, the obtained results ensure the predictive ability of the developed QSAR model for the design of new high-potency benzodiazepine drugs.


Supplementary information:

The online version contains supplementary material available at 10.1007/s11224-022-02029-4.


Keywords:

Benzodiazepine; Chloride channel; Extracellular domain; GABAA receptor; TM2 helix; Transmembrane domain.

Conflict of interest statement

Conflict of interestThe authors declare no competing interests.

Figures



Fig. 1

Binding sites of the two endogenous agonists (GABA) and diazepam. a ECD interface for the binding of diazepam (a) and GABA (a’ and a’’). b The three TMD interfaces identified for the binding of diazepam [7]


Fig. 2


Fig. 2

Binding modes resulting from the molecular docking of Ro12-6377and proflazepam at the interfaces of a ECD

α1+

/

γ2

, b TMD

β2+(A)

/

α1(B)

, c TMD

β2+(C)

/

α1(D)

, and d TMD

γ2+

/

β2


Fig. 3


Fig. 3

Binding interactions resulting from the molecular docking of Ro126377 at the interfaces of a ECD

α1+

/

γ2

, b TMD

β2+(A)

/

α1(B)

, c TMD

β2+(C)

/

α1(D)

, and d TMD

γ2+

/

β2


Fig. 4


Fig. 4

Binding interactions resulting from the molecular docking of proflazepam atthe interfaces of a ECD

α1+

/

γ2

, b TMD

β2+(A)

/

α1B

, c TMD

β2+(C)

/

α1(D)

, and d TMD

γ2+

/

β2


Fig. 5


Fig. 5

Evaluation the response of potential energy, U (kcal/mol), as function of time, t(ps), for Ro126377 and proflazepam in complex with a ECD

α1+

/

γ2

, b TMD

β2+(A)

/

α1(B)

, c TMD

β2+(C)

/

α1(D)

, and d TMD

γ2+

/

β2

interfaces


Fig. 6


Fig. 6

Binding modes resulting from the molecular dynamics simulation of Ro126377 at the interfaces of a ECD

α1+

/

γ2

, b TMD

β2+(A)

/

α1(B)

, c TMD

β2+(C)

/

α1(D)

, and d TMD

γ2+

/

β2

interfaces


Fig.7


Fig.7

Binding interactions resulting from the molecular dynamics simulation of Ro126377 atthe interfaces of a ECD

α1+

/

γ2

, b TMD

β2+(A)

/

α1(B)

, c TMD

β2+(C)

/

α1(D)

, and d TMD

γ2+

/

β2

interfaces


Fig. 8


Fig. 8

Binding modes resulting from the molecular dynamics simulation of proflazepam at the interfaces of a ECD

α1+

/

γ2

, b TMD

β2+(A)

/

α1(B)

, c TMD

β2+(C)

/

α1(D)

, and d TMD

γ2+

/

β2

interfaces


Fig. 9


Fig. 9

Binding interactions resulting from the molecular dynamics simulation of proflazepam at the interfaces of a ECD

α1+

/

γ2

, b TMD

β2+(A)

/

α1(B)

, c TMD

β2+(C)

/

α1(D)

, and d TMD

γ2+

/

β2

interface


Fig. 10


Fig. 10

Box plots of the distribution of the Bayesian Information Criterion (BIC) by number of molecular descriptors


Fig. 11


Fig. 11

Probability of occurrence of selected molecular descriptors

Similar articles

References

    1. Bergmann R, Kongsbak K, Sørensen PL, Sander T, Balle T (2013) A unified model of the GABAA receptor comprising agonist and benzodiazepine binding sites. PLoS One 8. 10.1371/journal.pone.0052323



      PMC



      PubMed

    1. Zhu S, Noviello CM, Teng J, Walsh RM, Kim JJ, Hibbs RE. Structure of a human synaptic GABAA receptor. Nature. 2018;559:67–88. doi: 10.1038/s41586-018-0255-3.



      DOI



      PMC



      PubMed

    1. Sigel E, Steinmann ME. Structure, function, and modulation of GABAA receptors. J Biol Chem. 2012;287:40224–40231. doi: 10.1074/jbc.R112.386664.



      DOI



      PMC



      PubMed

    1. Miller PS, Aricescu AR. Crystal structure of a human GABAA receptor. Nature. 2014;512:270–275. doi: 10.1038/nature13293.



      DOI



      PMC



      PubMed

    1. Olsen RW, Sieghart W (2008) International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit composition, pharmacology, and function. Update Pharmacol Rev 60:243–260. 10.1124/pr.108.00505



      PMC



      PubMed



Source link

EHS
Back to top button