In silico development of potential therapeutic for the pain treatment by inhibiting voltage-gated sodium channel 1.7

Golubović, Mlađjan; Kostić, Tomislav; Djordjevic, Miodrag; Perić, Velimir; Lazarević, Milan; Milić, Dragan; Marjanović, Vesna; Veselinović, Aleksandar M.

doi:10.1016/j.compbiomed.2021.104346

Cited by 5 publications

(3 citation statements)

References 38 publications

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“…The best 3D‐QSAR model exhibited an outstanding linear correlation between the experimental activities and the predicted values. Moreover, Golubovic et al used the Monte Carlo method to build a 3D field‐based QSAR model for a series of aryl sulfonamide Na v 1.7 inhibitors 76 . A group of 45 inhibitors, with IC 50 values ranging from 0.3 to 2300 nM, were divided into the training set (34 compounds) and test set (11 compounds).…”

Section: Drug Design Based On Caddmentioning

confidence: 99%

“…Moreover, Golubovic et al used the Monte Carlo method to build a 3D field-based QSAR model for a series of aryl sulfonamide Na v 1.7 inhibitors. 76 A group of 45 inhibitors, with IC 50 values ranging from 0.3 to 2300 nM, were divided into the training set (34 compounds) and test set (11 compounds). The hNa v 1.7-VSD4-Na v Ab structure was used in molecular docking studies to verify the reliability of the developed model.…”

Section: Qsar Analysismentioning

confidence: 99%

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Recent advances in computational studies on voltage‐gated sodium channels: Drug design and mechanism studies

Wang

Chen

et al. 2022

WIREs Comput Mol Sci

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Voltage-gated sodium channels (VGSCs/Na v s), which control the flow of Na + and affect the generation of action potentials (APs), have been regarded as essential targets for many diseases. The biological and pharmacological functions of VGSCs have been extensively studied and many efforts have been made to discover and design ligands of VGSCs as potential therapies. Here, we summarize the recent and representative studies of VGSCs from the perspective of computer-aided drug design (CADD) and molecular modeling, including the structural biology of VGSCs, virtual screening and drug design toward VGSCs based on CADD, and functional studies using molecular modeling technologies. Furthermore, we conclude the achievements that have been made in the field of VGSCs and discuss the shortcomings found in previous studies. We hope that this review can provide some inspiration and reference for future investigations of VGSCs and drug design. This article is categorized under:Structure and Mechanism > Computational Biochemistry and Biophysicscomputer-aided drug design, molecular dynamic simulation, structural biology, voltage-gated sodium channels | INTRODUCTIONVoltage-gated sodium channels (VGSCs/Na v s) are widely expressed in eukaryotes and prokaryotes, and play especially important roles in the generation and propagation of action potentials (APs). 1,2 Since Hodgkin and Huxley successfully recorded the first Na + -based APs from the giant axons of the squid Loligo, 3,4 researchers came to realize the important role of VGSCs in nerve impulse conduction, which opened a new door for VGSCs studies. To date, 10 subtypes of VGSCs (Na v 1.1-Na v 1.9 and Nax) have been found in mammals, and each subtype has its own unique functions (Table S1). Na v 1.1, Na v 1.2, Na v 1.3, and Na v 1.6 are primarily expressed in the central nervous system (CNS), and associated with many diseases such as epilepsy, migraine, autism, and ataxia. 5 Na v 1.4 is predominantly expressed in skeletal

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Section: Drug Design Based On Caddmentioning

confidence: 99%

Section: Qsar Analysismentioning

confidence: 99%

Recent advances in computational studies on voltage‐gated sodium channels: Drug design and mechanism studies

Wang

Chen

et al. 2022

WIREs Comput Mol Sci

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“…There is also considerable interest in various sulfonamide analogs which display selectivity toward Na v 1.7 and are effective in pain mitigation in animal models [ (178)(179)(180)(181)(182)(183); see Table 1]. Therapeutic concentrations of the inactivated state blocker PF-05089771 increase the rheobase of control neurons, but not that of Na v 1.7 knock-out neurons.…”

Section: Pharmacological Manipulation Of Na V 17mentioning

confidence: 99%

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Alles

Smith

2021

Front. Pain Res.

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The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects. Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K+ channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na+ channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca2+ channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing “pain” as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.

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Identification of key candidate genes and biological pathways in neuropathic pain

Cui

Liu

Peng

et al. 2022

Computers in Biology and Medicine

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In silico development of potential therapeutic for the pain treatment by inhibiting voltage-gated sodium channel 1.7

Cited by 5 publications

References 38 publications

Recent advances in computational studies on voltage‐gated sodium channels: Drug design and mechanism studies

Recent advances in computational studies on voltage‐gated sodium channels: Drug design and mechanism studies

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Identification of key candidate genes and biological pathways in neuropathic pain

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