Phenytoin (PHT) and Carbamazepine (CBZ) are excellent sodium channel blockers administered in clinical treatment of epileptic
seizures. However, the narrow therapeutic range and limited pharmacokinetics of these drugs have raised serious concerns in the
proper management of epilepsy. To overcome this, the present study attempts to identify a candidate molecule with superior
pharmacological profile than PHT and CBZ through In silico approaches. PHT and CBZ served as query small molecules for
Tanimoto based similarity search with a threshold of 95% against PubChem database. Aided by MolDock algorithm, high affinity
similar compound against each query was retrieved. PHT and CBZ and their respective similar were further tested for toxicity
profiles, LC 50 values and biological activity. Compounds, NSC403438 and AGN-PC-0BPCBP respectively similar to PHT and CBZ
demonstrated higher affinity to sodium channel protein than their respective leads. Of particular relevance, NSC403438
demonstrated highest binding affinity bestowed with least toxicity, better LC 50 values and optimal bioactivity. NSC403438 was
further mapped for its structure based pharmacophoric features. In the study, we report NSC403438 as potential sodium channel
blocker as a better candidate than PHT and CBZ which can be put forth for pharmacodynamic and pharmacokinetic studies.AbbreviationsAEDs - Antiepileptic drugs,
BLAST - Basic Local Alignment Search Tool,
CBZ - Carbamazepine,
GEFS+ - Generalized Epilepsy with Febrile Seizures Plus,
GPCR - G Protein Coupled Receptor,
Nav - Sodium channel with specific voltage conduction,
PDB - Protein Data Bank,
PHT - Phenytoin,
PIR - Protein Information resources,
SAVES - Structural Analysis and Verification Server,
VGSC - Voltage-gated Sodium channels.
miRNAs are fascinating molecular players for gene regulation as individual miRNA can control multiple targets and a single target can be regulated by multiple miRNAs. Loss of miRNA regulated gene expression is often reported to be implicated in various human diseases like diabetes and cancer. Recently, geneticists across the world started reporting single nucleotide polymorphism (SNPs) in seed sequences of miRNAs. Similarly, SNPs are also reported in various target sequences of these miRNAs. Both the scenarios lead to dysregulated gene expression which may result in the progression of diseases. In the present paper, we explore SNPs in various miRNAs and their target sequences reported in various human cancers as well as diabetes. Similarly, we also present evidence of these mutations in various other human diseases.
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