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Computer aided identification of sodium channel blockers in the clinical treatment of epilepsy using molecular docking tools.

Shaheen U, Akka J, Hinore JS, Girdhar A, Bandaru S, Sumithnath TG, Nayarisseri A, Munshi A - Bioinformation (2015)

Bottom Line: To overcome this, the present study attempts to identify a candidate molecule with superior pharmacological profile than PHT and CBZ through In silico approaches.Of particular relevance, NSC403438 demonstrated highest binding affinity bestowed with least toxicity, better LC 50 values and optimal bioactivity.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, Telangana, India.

ABSTRACT

Unlabelled: 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.

Abbreviations: AEDs - 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.

No MeSH data available.


Related in: MedlinePlus

Structure of A) NSC403438 (CID: 345700) - compoundsimilar to PHT; B) AGN-PC-0BPCBP (CID: 57199333) -compound similar to CBZ
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Related In: Results  -  Collection


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Figure 2: Structure of A) NSC403438 (CID: 345700) - compoundsimilar to PHT; B) AGN-PC-0BPCBP (CID: 57199333) -compound similar to CBZ

Mentions: Number of similar compounds screened with ≥95 similaritycorresponding to each PHT and CBZ has been listed in Table 3(see supplementary material). The procheck results revealed the modified status of the modeled structure of SCN1A protein(Figure 1A). In final model 97.6 percentages of overall aminoacids were in allowed region of Ramachandran plot, validatingthe model in close proximate to experimental quality. Evidentfrom rerank score, compound NSC403438 (CID: 345700)(Figure 2a) showed 1.47 folds better interaction than PHTwhereas; compound AGN-PC-0BPCBP (CID: 57199333)(Figure 2b) was 1.29 folds better interacting compound thanCBZ (Table 3). In further investigation we observed thatcompound NSC403438 was marginally (1.4 folds) betterinteracting drug than AGN-PC-0BPCBP Table 3 (seesupplementary material). NSC403438 not only showed betterinteraction against the channel than its parent compound PHT,but also showed superior binding affinity than CBZ and rest ofthe virtually screened molecules (Table 3). The overallinteraction profile of PHT, CBZ and their respective similarNSC403438 and AGN-PC-0BPCBP is shown in Table 4 (seesupplementary material). The superior rerank score ofNSC403438 can be probably attributed to its optimalelectrostatic and hydrogen bond interactions Table 4 (seesupplementary material). The LC 50 values at 96 hour intervalwere predicted to be 1.6 folds superior for NSC403438 than its parent compound PHT; similarly AGN-PC-0BPCBP had 2.4folds better LC 50 values than CBZ Table 5 (seesupplementary material). In addition the similar compoundsidentified against their parents showed enhanced bioactivityproviding a clue for target specificity Table 5 (seesupplementary material). Except for AGN-PC-0BPCBP, all thecompounds were safe and predicted to be non-carcinogen andnon-mutagenic Table 6 (see supplementary material). Further,results from ADMET prediction revealed that NSC403438 to bebetter drug like compound compared to AGN-PC-0BPCBPTable 7 (see supplementary material). In the present study,we were able to identify similar compounds to have betterpharmacological profile than their parents, however, CBZsimilar - AGN-PC-0BPCBP failed to pass carcinogenic filter incell lines of DBS Hamster. Taking this fact into consideration,only PHT similar - NSC403438 was mapped for its structurebased pharmacophoric features. Comprehensively shown infigure 3a, the molecule demonstrated van der Waalsinteractions with His 614, Pro 611, Arg 500, Leu 716, Arg 501and Asp 606 and electrostatic interactions with Gln 554, His553 Ser 607, 550 and 603, Val 610, Asn 499 and Arg 498. Furtherπ- π interactions were observed with Arg 501 and 498. Theligand binding pattern of NSC403438 in the channel site isshown in Figure 3b. Electrostatic and hydrophobic interactionsof NSC403438 in the channel is shown in Figure 4a & Figure 4brespectively.


Computer aided identification of sodium channel blockers in the clinical treatment of epilepsy using molecular docking tools.

Shaheen U, Akka J, Hinore JS, Girdhar A, Bandaru S, Sumithnath TG, Nayarisseri A, Munshi A - Bioinformation (2015)

Structure of A) NSC403438 (CID: 345700) - compoundsimilar to PHT; B) AGN-PC-0BPCBP (CID: 57199333) -compound similar to CBZ
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4403034&req=5

Figure 2: Structure of A) NSC403438 (CID: 345700) - compoundsimilar to PHT; B) AGN-PC-0BPCBP (CID: 57199333) -compound similar to CBZ
Mentions: Number of similar compounds screened with ≥95 similaritycorresponding to each PHT and CBZ has been listed in Table 3(see supplementary material). The procheck results revealed the modified status of the modeled structure of SCN1A protein(Figure 1A). In final model 97.6 percentages of overall aminoacids were in allowed region of Ramachandran plot, validatingthe model in close proximate to experimental quality. Evidentfrom rerank score, compound NSC403438 (CID: 345700)(Figure 2a) showed 1.47 folds better interaction than PHTwhereas; compound AGN-PC-0BPCBP (CID: 57199333)(Figure 2b) was 1.29 folds better interacting compound thanCBZ (Table 3). In further investigation we observed thatcompound NSC403438 was marginally (1.4 folds) betterinteracting drug than AGN-PC-0BPCBP Table 3 (seesupplementary material). NSC403438 not only showed betterinteraction against the channel than its parent compound PHT,but also showed superior binding affinity than CBZ and rest ofthe virtually screened molecules (Table 3). The overallinteraction profile of PHT, CBZ and their respective similarNSC403438 and AGN-PC-0BPCBP is shown in Table 4 (seesupplementary material). The superior rerank score ofNSC403438 can be probably attributed to its optimalelectrostatic and hydrogen bond interactions Table 4 (seesupplementary material). The LC 50 values at 96 hour intervalwere predicted to be 1.6 folds superior for NSC403438 than its parent compound PHT; similarly AGN-PC-0BPCBP had 2.4folds better LC 50 values than CBZ Table 5 (seesupplementary material). In addition the similar compoundsidentified against their parents showed enhanced bioactivityproviding a clue for target specificity Table 5 (seesupplementary material). Except for AGN-PC-0BPCBP, all thecompounds were safe and predicted to be non-carcinogen andnon-mutagenic Table 6 (see supplementary material). Further,results from ADMET prediction revealed that NSC403438 to bebetter drug like compound compared to AGN-PC-0BPCBPTable 7 (see supplementary material). In the present study,we were able to identify similar compounds to have betterpharmacological profile than their parents, however, CBZsimilar - AGN-PC-0BPCBP failed to pass carcinogenic filter incell lines of DBS Hamster. Taking this fact into consideration,only PHT similar - NSC403438 was mapped for its structurebased pharmacophoric features. Comprehensively shown infigure 3a, the molecule demonstrated van der Waalsinteractions with His 614, Pro 611, Arg 500, Leu 716, Arg 501and Asp 606 and electrostatic interactions with Gln 554, His553 Ser 607, 550 and 603, Val 610, Asn 499 and Arg 498. Furtherπ- π interactions were observed with Arg 501 and 498. Theligand binding pattern of NSC403438 in the channel site isshown in Figure 3b. Electrostatic and hydrophobic interactionsof NSC403438 in the channel is shown in Figure 4a & Figure 4brespectively.

Bottom Line: To overcome this, the present study attempts to identify a candidate molecule with superior pharmacological profile than PHT and CBZ through In silico approaches.Of particular relevance, NSC403438 demonstrated highest binding affinity bestowed with least toxicity, better LC 50 values and optimal bioactivity.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, Telangana, India.

ABSTRACT

Unlabelled: 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.

Abbreviations: AEDs - 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.

No MeSH data available.


Related in: MedlinePlus