Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter

Dı́az, José Luis; Cuevas, Félix; Pazos, Gonzalo; Álvarez-Bercedo, Paula; Oliva, Ana I.; Sarmentero, M. Angeles; Font, David García; Jiménez-Aquino, Agustín; Moron, Maria; Port, Adriana; Pascual, Rosalía; Dordal, Alberto; Portillo‐Salido, Enrique; Reinoso, Raquel F.; Vela, José Miguel; Almansa, Carmen

doi:10.1021/acs.jmedchem.0c01867

Cited by 6 publications

(4 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A similar strategy was used to discover the potential inhibitors for sodium-glucose cotransporter-2 (SGLT2, SLC5A2) . Additionally, docking was used to reveal the potential binding sites , or investigate the interacting mechanism of ligands on targets, such as apical sodium-dependent bile acid transporter (ASBT, SLC10A2), norepinephrine transporter (NET), organic cation transporter 1 (OCT1, SLC22A1), and so on. , More recently, a systematic structure-based method combing Gaussian-accelerated molecular dynamics (GaMD) simulation and docking was performed to explore allosteric sites on DAT in inward-open conformation and to screen hit compounds with allosteric affinity . Meanwhile, docking of 200 million small molecules against the inward-open state of the SERT identified lead compound stabilized an outward-closed state of the SERT with little activity against common off-targets which confirmed by cryo-EM structure …”

Section: Drug Design Targeting Slcsmentioning

confidence: 99%

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Tu,

Fu,

Zheng

et al. 2024

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Solute carrier transporters (SLCs) are a class of important transmembrane proteins that are involved in the transportation of diverse solute ions and small molecules into cells. There are approximately 450 SLCs within the human body, and more than a quarter of them are emerging as attractive therapeutic targets for multiple complex diseases, e.g., depression, cancer, and diabetes. However, only 44 unique transporters (∼9.8% of the SLC superfamily) with 3D structures and specific binding sites have been reported. To design innovative and effective drugs targeting diverse SLCs, there are a number of obstacles that need to be overcome. However, computational chemistry, including physics-based molecular modeling and machine learning-and deep learning-based artificial intelligence (AI), provides an alternative and complementary way to the classical drug discovery approach. Here, we present a comprehensive overview on recent advances and existing challenges of the computational techniques in structure-based drug design of SLCs from three main aspects: (i) characterizing multiple conformations of the proteins during the functional process of transportation, (ii) identifying druggability sites especially the cryptic allosteric ones on the transporters for substrates and drugs binding, and (iii) discovering diverse small molecules or synthetic protein binders targeting the binding sites. This work is expected to provide guidelines for a deep understanding of the structure and function of the SLC superfamily to facilitate rational design of novel modulators of the transporters with the aid of state-of-the-art computational chemistry technologies including artificial intelligence.

show abstract

Section: Drug Design Targeting Slcsmentioning

confidence: 99%

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Tu,

Fu,

Zheng

et al. 2024

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…137 Di ́az et al designed a dual-target inhibitor (64) that acts on the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the norepinephrine transporter (NET), two mechanisms in the treatment of pain. 138 The pyrimidodiazepinone nucleus of compound 63 was selected for fusing with the more homogeneous NET pharmacophore (62).…”

Section: Rational Design Of Multitargeted Ligandsmentioning

confidence: 99%

Rational Multitargeted Drug Design Strategy from the Perspective of a Medicinal Chemist

Liu

et al. 2021

J. Med. Chem.

View full text Add to dashboard Cite

The development of multitarget-directed ligands (MTDLs) has become a widely focused research topic, but rational design remains as an enormous challenge. This paper reviews and discusses the design strategy of incorporating the second activity into an existing single-active ligand. If the binding sites of both targets share similar endogenous substrates, MTDLs can be designed by merging two lead compounds with similar functional groups. If the binding sites are large or adjacent to the solution, two key pharmacophores can be fused directly. If the binding regions are small and deep inside the proteins, the linkedpharmacophore strategy might be the only way. The added pharmacophores of second targets should not affect the binding mode of the original ones. Moreover, the inhibitory activities of the two targets need to be adjusted to achieve an optimal ratio.

show abstract

“…These have been summarized elsewhere 22 and in our recent work describing a new family of bicyclic diazepinones as dual ligands of the Ca v α2δ-1 and the norepinephrine transporter. 23 We describe here the structure−activity relationship (SAR) study that led from the HTS hit 2 to the identification of the highly selective derivative 16RR, through a process summarized in Figure 1 and outlined below.…”

mentioning

confidence: 99%

Piperazinyl Bicyclic Derivatives as Selective Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels

Fernández¹,

Dı́az²,

Garcia³

et al. 2021

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

The synthesis and pharmacological activities of a new series of piperazinyl quinazolin-4-(3H)-one derivatives acting toward the α2δ-1 subunit of voltage-gated calcium channels (Ca v α2δ-1) are reported. Different positions of a micromolar HTS hit were explored, and best activities were obtained for compounds containing a small alkyl group in position 3 of the quinazolin-4-(3H)-one scaffold and a 3-methyl-piperazin-1-yl-or 3,5-dimethylpiperazin-1-yl-butyl group in position 2. The activity was shown to reside in the R enantiomer of the chain in position 2, and several eutomers reached single digit nanomolar affinities. Final modification of the central scaffold to reduce lipophilicity provided the pyrido [4,3-d]pyrimidin-4(3H)-one 16RR, which showed high selectivity for Ca v α2δ-1 versus Ca v α2δ-2, probably linked to its improved analgesic efficacy-safety ratio in mice over pregabalin.

show abstract

Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter

Cited by 6 publications

References 43 publications

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Computational Chemistry in Structure-Based Solute Carrier Transporter Drug Design: Recent Advances and Future Perspectives

Rational Multitargeted Drug Design Strategy from the Perspective of a Medicinal Chemist

Piperazinyl Bicyclic Derivatives as Selective Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels

Contact Info

Product

Resources

About