In Silico Drug Repurposing Framework Predicts Repaglinide, Agomelatine and Protokylol as TRPV1 Modulators with Analgesic Activity

Andrei, Corina; Mihai, Dragoș Paul; Zanfirescu, Anca; Nițulescu, George Mihai; Negreş, Simona

doi:10.3390/pharmaceutics14122563

Cited by 5 publications

(4 citation statements)

References 80 publications

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“…Currently, the vast majority of drug discoveries of TRPV1 channel modulators stem from traditional drug design methods. In the few applications of VS, Llanos (Llanos et al, 2022) and Andrei (Andrei et al, 2022) both used a strategy of drug repurposing to perform virtual screening on the DrugBank database. Our research used multiple compounds databases, and three hits were found through LBVS and SBVS methods.…”

Section: Discussionmentioning

confidence: 99%

Discovery of novel TRPV1 modulators through machine learning‐based molecular docking and molecular similarity searching

Wei¹,

Yang²,

Yang³

et al. 2023

Chem Biol Drug Des

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The transient receptor potential vanilloid 1 (TRPV1) channel belongs to the transient receptor potential channel superfamily and participates in many physiological processes. TRPV1 modulators (both agonists and antagonists) can effectively inhibit pain caused by various factors and have curative effects in various diseases, such as itch, cancer, and cardiovascular diseases. Therefore, the development of TRPV1 channel modulators is of great importance. In this study, the structure‐based virtual screening and ligand‐based virtual screening methods were used to screen compound databases respectively. In the structure‐based virtual screening route, a full‐length human TRPV1 protein was first constructed, three molecular docking methods with different precisions were performed based on the hTRPV1 structure, and a machine learning‐based rescoring model by the XGBoost algorithm was constructed to enrich active compounds. In the ligand‐based virtual screening route, the ROCS program was used for 3D shape similarity searching and the EON program was used for electrostatic similarity searching. Final 77 compounds were selected from two routes for in vitro assays. The results showed that 8 of them were identified as active compounds, including three hits with IC50 values close to capsazepine. In addition, one hit is a partial agonist with both agonistic and antagonistic activity. The mechanisms of some active compounds were investigated by molecular dynamics simulation, which explained their agonism or antagonism.

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Section: Discussionmentioning

confidence: 99%

Discovery of novel TRPV1 modulators through machine learning‐based molecular docking and molecular similarity searching

Wei¹,

Yang²,

Yang³

et al. 2023

Chem Biol Drug Des

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“…The ChEMBL database includes currently data for ~2.3 million ligands and ~15,000 targets, which were collected from published assays, scientific publications, or gathered from other databases and research institutions across the world [102,103]. Screening experiments on ion channels often exploit the ChEMBL ion channel dataset [104,105]. One can specify a particular ion channel family and subtype and obtain a list of small molecule ligands that are known to act on these targets.…”

Section: Virtual Ligand Libraries For Ion Channel Drug Discoverymentioning

confidence: 99%

Recent Advances in Computer-Aided Structure-Based Drug Design on Ion Channels

Pliushcheuskaya,

Künze

2023

IJMS

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Ion channels play important roles in fundamental biological processes, such as electric signaling in cells, muscle contraction, hormone secretion, and regulation of the immune response. Targeting ion channels with drugs represents a treatment option for neurological and cardiovascular diseases, muscular degradation disorders, and pathologies related to disturbed pain sensation. While there are more than 300 different ion channels in the human organism, drugs have been developed only for some of them and currently available drugs lack selectivity. Computational approaches are an indispensable tool for drug discovery and can speed up, especially, the early development stages of lead identification and optimization. The number of molecular structures of ion channels has considerably increased over the last ten years, providing new opportunities for structure-based drug development. This review summarizes important knowledge about ion channel classification, structure, mechanisms, and pathology with the main focus on recent developments in the field of computer-aided, structure-based drug design on ion channels. We highlight studies that link structural data with modeling and chemoinformatic approaches for the identification and characterization of new molecules targeting ion channels. These approaches hold great potential to advance research on ion channel drugs in the future.

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“…79 Table 1 represents the progress of various TRP modulators in the clinical context. 43,[80][81][82][83][84][85][86][87][88]…”

Section: Trpm8 As a Drug Targetmentioning

confidence: 99%

A Comprehensive Review on the Regulatory Action of TRP Channels: A Potential Therapeutic Target for Nociceptive Pain

Anand,

Rajagopal

2023

J Exp Neurosci

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The transient receptor potential (TRP) superfamily of ion channels in humans comprises voltage-gated, non-selective cation channels expressed both in excitable as well as non-excitable cells. Four TRP channel subunits associate to create functional homo- or heterotetramers that allow the influx of calcium, sodium, and/or potassium. These channels are highly abundant in the brain and kidney and are important mediators of diverse biological functions including thermosensation, vascular tone, flow sensing in the kidney and irritant stimuli sensing. Inherited or acquired dysfunction of TRP channels influences cellular functions and signaling pathways resulting in multifaceted disorders affecting skeletal, renal, cardiovascular, and nervous systems. Studies have demonstrated the involvement of these channels in the generation and transduction of pain. Based on the multifaceted role orchestrated by these TRP channels, modulation of the activity of these channels presents an important strategy to influence cellular function by regulating intracellular calcium levels as well as membrane excitability. Therefore, there has been a remarkable pharmaceutical inclination toward TRP channels as therapeutic interventions. Several candidate drugs influencing the activity of these channels are already in the clinical trials pipeline. The present review encompasses the current understanding of TRP channels and TRP modulators in pain and pain management.

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In Silico Drug Repurposing Framework Predicts Repaglinide, Agomelatine and Protokylol as TRPV1 Modulators with Analgesic Activity

Cited by 5 publications

References 80 publications

Discovery of novel TRPV1 modulators through machine learning‐based molecular docking and molecular similarity searching

Discovery of novel TRPV1 modulators through machine learning‐based molecular docking and molecular similarity searching

Recent Advances in Computer-Aided Structure-Based Drug Design on Ion Channels

A Comprehensive Review on the Regulatory Action of TRP Channels: A Potential Therapeutic Target for Nociceptive Pain

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