Pharmacophore models for GABA<sub>A</sub>modulators: implications in CNS drug discovery

Ghoshal, Nanda; Vijayan, Ramachandran

doi:10.1517/17460441003789363

Cited by 6 publications

(5 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, previous pharmacophore models disagree on which should be the exact charge-charge distance in GABA A agonists. However, it has generally been proposed to be in the range 4–5 Å [11] and in fact, our GABA A R model predicts that agonist with different inter-charge distances (4–5 Å) may bind equally well to the receptor. Apart from the salt bridge to β 2 E155, the positive charge of GABA is further surrounded by the aromatic ring of β 2 Y205 and makes a hydrogen bond to the backbone β 2 S156 (B-loop) similar to glutamate in the GluCl template structure.…”

Section: Resultsmentioning

confidence: 69%

“…The model is capable of explaining SARs, mutational data, and data from studies of covalent linking of a DZP-derivative to cysteine mutants of the receptor. Therefore, the validated model might also serve as a tool for structure guided design of new agonists and allosteric modulators and may form the link to interpretation of previously reported pharmacophore models [11], [14], [39] in a structural context.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

et al. 2013

View full text Add to dashboard Cite

We present a full-length α1β2γ2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans and includes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Available mutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest a GABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predicted with residues α1R66, β2T202, α1T129, β2E155, β2Y205 and the backbone of β2S156. Muscimol is predicted to bind similarly, however, with minor differences rationalized with quantum mechanical energy calculations. Muscimol key interactions are predicted to be α1R66, β2T202, α1T129, β2E155, β2Y205 and β2F200. Furthermore, we argue that a water molecule could mediate further interactions between muscimol and the backbone of β2S156 and β2Y157. DZP is predicted to bind with interactions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interact with two threonines α1T206 and γ2T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near the important α1H101 and the N-methyl group near α1Y159, α1T206, and α1Y209. We present a binding mode of DZP in which the pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full length GABAA receptor is made available as Model S1.

show abstract

Section: Resultsmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

et al. 2013

View full text Add to dashboard Cite

show abstract

“…This rationalizes why ZPM exerts a sedative/hypnotic pharmacological profile. Very little is known about the structural requirements for Zolpidem binding as structural investigations on GABA A receptor ionophore complex is precluded due to a host of issues like large size (∼50 kD), heterogeneity, low abundance (pmol mg -1 of protein), together with other inherent difficulties associated in isolation and purification of integral membrane proteins [10].…”

mentioning

confidence: 99%

Deciphering the binding mode of Zolpidem to GABAA α1 receptor – insights from molecular dynamics simulation

2011

Self Cite

View full text Add to dashboard Cite

To investigate the binding mode of Zolpidem to GABA(A) and to delineate the conformational changes induced upon agonist binding, we carried out atomistic molecular dynamics simulation using the ligand binding domain of GABA(A) α(1) receptor. Comparative molecular dynamics simulation of the apo and the holo form of GABA(A) receptor revealed that γ(2)/α(1) interface housing the benzodiazepine binding site undergoes distinct conformational changes upon Zolpidem binding. We notice that C loop of the α(1) subunit experiences an inward motion toward the vestibule and the F loop of γ(2) sways away from the vestibule, an observation that rationalizes Zolpidem as an alpha1 selective agonist. Energy decomposition analysis carried out was able to highlight the important residues implicated in Zolpidem binding, which were largely in congruence with the experimental data. The simulation study disclosed herein provides a meaningful insight into Zolpidem-GABA(A)R interactions and helps to arrive at a binding mode hypothesis with implications for drug design.

show abstract

“…Pharmacophore models describe the vital molecular features and their spatial arrangement of ligand–protein interactions and are a fast and efficient method for virtual screening (VS) active drug molecules [ 19 , 20 ]. Despite the significant advances, the pharmacophore approach still faces several challenges, such as the low efficiency of screening large chemical databases with flexible molecules and high false positive/negative rates due to model quality issues [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Discovery of novel JAK1 inhibitors through combining machine learning, structure-based pharmacophore modeling and bio-evaluation

Wang,

Sun,

et al. 2023

J Transl Med

View full text Add to dashboard Cite

Background Janus kinase 1 (JAK1) plays a critical role in most cytokine-mediated inflammatory, autoimmune responses and various cancers via the JAK/STAT signaling pathway. Inhibition of JAK1 is therefore an attractive therapeutic strategy for several diseases. Recently, high-performance machine learning techniques have been increasingly applied in virtual screening to develop new kinase inhibitors. Our study aimed to develop a novel layered virtual screening method based on machine learning (ML) and pharmacophore models to identify the potential JAK1 inhibitors. Methods Firstly, we constructed a high-quality dataset comprising 3834 JAK1 inhibitors and 12,230 decoys, followed by establishing a series of classification models based on a combination of three molecular descriptors and six ML algorithms. To further screen potential compounds, we constructed several pharmacophore models based on Hiphop and receptor-ligand algorithms. We then used molecular docking to filter the recognized compounds. Finally, the binding stability and enzyme inhibition activity of the identified compounds were assessed by molecular dynamics (MD) simulations and in vitro enzyme activity tests. Results The best performance ML model DNN-ECFP4 and two pharmacophore models Hiphop3 and 6TPF 08 were utilized to screen the ZINC database. A total of 13 potentially active compounds were screened and the MD results demonstrated that all of the above molecules could bind with JAK1 stably in dynamic conditions. Among the shortlisted compounds, the four purchasable compounds demonstrated significant kinase inhibition activity, with Z-10 being the most active (IC50 = 194.9 nM). Conclusion The current study provides an efficient and accurate integrated model. The hit compounds were promising candidates for the further development of novel JAK1 inhibitors.

show abstract

Pharmacophore models for GABA_Amodulators: implications in CNS drug discovery

Cited by 6 publications

References 77 publications

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

Deciphering the binding mode of Zolpidem to GABAA α1 receptor – insights from molecular dynamics simulation

Discovery of novel JAK1 inhibitors through combining machine learning, structure-based pharmacophore modeling and bio-evaluation

Contact Info

Product

Resources

About

Pharmacophore models for GABAAmodulators: implications in CNS drug discovery

Cited by 6 publications

References 77 publications

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

Deciphering the binding mode of Zolpidem to GABAA α1 receptor – insights from molecular dynamics simulation

Discovery of novel JAK1 inhibitors through combining machine learning, structure-based pharmacophore modeling and bio-evaluation

Contact Info

Product

Resources

About

Pharmacophore models for GABA_Amodulators: implications in CNS drug discovery