shikhar gupta - Academia.edu (original) (raw)

Papers by shikhar gupta

Research paper thumbnail of Biomimetic Stratum Corneum Liposome Models: Lamellar Organization and Permeability Studies

Membranes

The stratum corneum (SC), the outer layer of the skin, plays a crucial role as a barrier protecti... more The stratum corneum (SC), the outer layer of the skin, plays a crucial role as a barrier protecting the underlying cells from external stress. The SC comprises three key components: ceramide (CER), free fatty acid (FFA), and cholesterol, along with small fractions of cholesterol sulfate and cholesterol ester. In order to gain a deeper understanding about the interdependence of the two major components, CER and FFA, on the organizational, structural, and functional properties of the SC layer, a library of SC lipid liposome (SCLL) models was developed by mixing CER (phytosphingosine or sphingosine), FFA (oleic acid, palmitic acid, or stearic acid), cholesterol, and cholesterol sulfate. Self-assembly of the SC lipids into lamellar phases was first confirmed by small-angle X-ray scattering. Short periodicity and long periodicity phases were identified for SCLLs containing phytosphingosines and sphingosine CERs, respectively. Furthermore, unsaturation in the CER acyl and FFA chains reduc...

Research paper thumbnail of Research Paper Information rich Descriptors for Predicting P-Glycoprotein Substrates and Non- substrates: A Binary-QSAR approach

A highly probabilistic binary quantitative structur e-activity relationship (binary-QSAR) model h... more A highly probabilistic binary quantitative structur e-activity relationship (binary-QSAR) model has been developed to predict substrates and non-su bstrates of P-glycoprotein (Pgp). A total of 123 compounds, classified as Pgp substrates/non-substra tes, on the basis of the efflux ratio from Pgp monolayer efflux assays were selected in this study . Binary-QSAR model is developed on training set of 99 diverse compound s (36 substrates and 63 non-substrates) using 12 inf ormation rich descriptors. Solubility, Lipinski violation score, partition coefficient, CYP2D6 enzyme substrate probability etc. were some of the important descriptors used in developin g binary-QSAR model. This model showed excellent overall prediction accuracy of 100% on substrates a nd non-substrates for training set of 99 compounds. Further, the leave-one-out cross-validated predicti on accuracy was 96.9% on substrates and non- substrates. When applied to the test set of 24 comp ounds (8 substrates and 16 non-subst...

Research paper thumbnail of Information rich Descriptors for Predicting P-Glycoprotein Substrates and Nonsubstrates: A Binary-QSAR approach

A highly probabilistic binary quantitative structure-activity relationship (binary-QSAR) model ha... more A highly probabilistic binary quantitative structure-activity relationship (binary-QSAR) model has been developed to predict substrates and non-substrates of P-glycoprotein (Pgp). A total of 123 compounds, classified as Pgp substrates/non-substrates, on the basis of the efflux ratio from Pgp monolayer efflux assays were selected in this study. Binary-QSAR model is developed on training set of 99 diverse compounds (36 substrates and 63 non-substrates) using 12 information rich descriptors. Solubility, Lipinski violation score, partition coefficient, CYP2D6 enzyme substrate probability etc. were some of the important descriptors used in developing binary-QSAR model. This model showed excellent overall prediction accuracy of 100% on substrates and non-substrates for training set of 99 compounds. Further, the leave-one-out cross-validated prediction accuracy was 96.9% on substrates and nonsubstrates. When applied to the test set of 24 compounds (8 substrates and 16 non-substrates), mode...

Research paper thumbnail of QSAR Models towards Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease

Quantitative Structure-Activity Relationships in Drug Design, Predictive Toxicology, and Risk Assessment, 2015

Research paper thumbnail of 2D-QSAR, Docking Studies, and In Silico ADMET Prediction of Polyphenolic Acetates as Substrates for Protein Acetyltransferase Function of Glutamine Synthetase of Mycobacterium tuberculosis

ISRN Structural Biology, 2013

A novel transacetylase (TAase) function of glutamine synthetase (GS) in bacterial species such as... more A novel transacetylase (TAase) function of glutamine synthetase (GS) in bacterial species such asMycobacterium smegmatisandMycobacterium tuberculosisH37Rv was established by us, termed as mycobacterial TAase (MTAase). Several polyphenolic acetates (PAs) were found to be substrates for MTAase by inhibiting certain receptor proteins such as glutathione S-transferase by way of acetylation. The present work describes the descriptor-based 2D-QSAR studies developed for a series of PA synthesized by us and evaluated for MTAase and antimycobacterial activity using stepwise multiple linear regression method with the kinetic constants and the minimum inhibitory constant (MIC) as the dependent variables, to address the fact that TAase activity was leading to the antimycobacterial activity. Further, blind docking methods using AutoDock were carried out to study the interaction of potent PA with the crystal structure ofM. tuberculosisGS. PAs were predicted to bindM. tuberculosisGS on the protein...

Research paper thumbnail of Dual Binding Site and Selective Acetylcholinesterase Inhibitors Derived from Integrated Pharmacophore Models and Sequential Virtual Screening

BioMed Research International, 2014

In this study, we have employedin silicomethodology combining double pharmacophore based screenin... more In this study, we have employedin silicomethodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer’s randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predi...

Research paper thumbnail of Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques

Bioorganic Medicinal Chemistry Letters, Feb 1, 2011

Research paper thumbnail of Molecular Docking Guided Comparative GFA, G/PLS, SVM and ANN Models of Structurally Diverse Dual Binding Site Acetylcholinesterase Inhibitors

Molecular …, 2011

Recently discovered 42 AChE inhibitors binding at the catalytic and peripheral anionic site were ... more Recently discovered 42 AChE inhibitors binding at the catalytic and peripheral anionic site were identified on the basis of molecular docking approach, and its comparative quantitative structure-activity relationship (QSAR) models were developed. These structurally diverse inhibitors were obtained by our previously reported high-throughput in vitro screening technique using 384-well plate's assay based on colorimetric method of Ellman. QSAR models were developed using (i) genetic function algorithm, (ii) genetic partial least squares, (iii) support vector machine and (iv) artificial neural network techniques. The QSAR model robustness and significance was critically assessed using different cross-validation techniques on test data set. The generated QSAR models using thermodynamic, electrotopological and electronic descriptors showed that nonlinear methods are more robust than linear methods, and provide insight into the structural features of compounds that are important for AChE inhibition.

Research paper thumbnail of Miniaturization and Validation of the Ellman's Reaction Based Acetylcholinesterase Inhibitory Assay into 384Well Plate Format and Screening of a Chemical Library

Combinatorial Chemistry & High Throughput Screening, 2010

Research paper thumbnail of Antiobesity and lipid lowering effects of Glycyrrhiza chalcones: Experimental and computational studies

Research paper thumbnail of Inhibition of acetylcholinesterase by coumarins: The case of coumarin 106

Pharmacological Research, 2008

Research paper thumbnail of 3D-pharmacophore model based virtual screening to identify dual-binding site and selective acetylcholinesterase inhibitors

Medicinal Chemistry Research

The formation of β-amyloid plaques in the brain is a key neurodegenerative event in Alzheimer’s d... more The formation of β-amyloid plaques in the brain is a key neurodegenerative event in Alzheimer’s disease (AD). Interestingly, research on acetylcholinesterase (AChE) enzyme has increased due to findings supporting this enzyme involvement in the β-amyloid peptide fibril formation during AD pathogenesis. In this investigation, chemical features based 3D pharmacophore models were developed from structurally diverse xanthostigmine derivatives, known inhibitors of AChE enzyme, using 3D-QSAR pharmacophore generation module in Discovery Studio2.5 (DS2.5). The constructed pharmacophore models for AChE inhibitors was further cross-validated using test set and Cat-Scramble methodology. The best quantitative pharmacophore model Hypo1, was used for screening the chemical databases of small compounds including Specs, NCI, and IBScreen, to identify the new compounds that are presumably able to act as dual-binding site AChE inhibitors. The screened virtual hits were then subjected to the Lipinski’s rule of five, blood–brain barrier (BBB), PSA, LogS, percent human oral absorption, and toxicity analysis. Finally, 32 compounds were identified as potential leads against AChE enzyme, showing good estimated activities and promising ADMET properties. Molecular docking of these compounds using FlexX software showed catalytic and peripheral anionic binding site interactions, so called dual binding of the AChE enzyme. Docking study was also performed on butyrylcholinesterase in order to understand the compound selectivity. This study may assist in the discovery and design of novel dual binding site and selective AChE inhibitors with potent inhibitory activity.

Research paper thumbnail of Ligand-based molecular design of 4-benzylpiperidinealkylureas and amides as CCR3 antagonists

Journal of Molecular Modeling, 2010

Asthma is an inflammatory disease of the lungs. Clinical studies suggest that eotaxin and chemoki... more Asthma is an inflammatory disease of the lungs. Clinical studies suggest that eotaxin and chemokine receptor-3 (CCR3) play a primary role in the recruitment of eosinophils in allergic asthma. Development of novel and potent CCR3 antagonists could provide a novel mechanism for inhibition of this recruitment process, thereby preventing asthma. With the intention of designing new ligands with enhanced inhibitor potencies against CCR3, a 3D-QSAR CoMFA study was carried out on 41 4-benzylpiperidinealkylureas and amide derivatives. The best statistics of the developed CoMFA model were r 2 = 0.960, \( r_{cv}^2 = 0.589 \) , n = 32 for the training set and \( r_{pred}^2 = 0.619 \) , n = 9 for the test set. The generated 3D-QSAR contribution maps shed some light on the effects of the substitution pattern related to CCR3 antagonist activity.

Research paper thumbnail of Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques

Bioorganic & Medicinal Chemistry Letters, 2011

Research paper thumbnail of Homology Modeling of Human α2A-Adrenoceptor

Nature Precedings, 2009

... doi :10.1038/npre.2009.4106.1. 0 votes. Homology Modeling of Human α 2A -Adrenoceptor. Jignes... more ... doi :10.1038/npre.2009.4106.1. 0 votes. Homology Modeling of Human α 2A -Adrenoceptor. Jignesh Patel 1 , Gourja G 1 , Vivek Kumar 1 , Yogesh Narkhede 1 , Shikhar Gupta 1 & C. Gopi Mohan 1. Correspondence: (Login to view email address). ...

Research paper thumbnail of In silico approach to discover multi-target-directed ligands for the treatment of Alzheimer's disease

Research paper thumbnail of Biomimetic Stratum Corneum Liposome Models: Lamellar Organization and Permeability Studies

Membranes

The stratum corneum (SC), the outer layer of the skin, plays a crucial role as a barrier protecti... more The stratum corneum (SC), the outer layer of the skin, plays a crucial role as a barrier protecting the underlying cells from external stress. The SC comprises three key components: ceramide (CER), free fatty acid (FFA), and cholesterol, along with small fractions of cholesterol sulfate and cholesterol ester. In order to gain a deeper understanding about the interdependence of the two major components, CER and FFA, on the organizational, structural, and functional properties of the SC layer, a library of SC lipid liposome (SCLL) models was developed by mixing CER (phytosphingosine or sphingosine), FFA (oleic acid, palmitic acid, or stearic acid), cholesterol, and cholesterol sulfate. Self-assembly of the SC lipids into lamellar phases was first confirmed by small-angle X-ray scattering. Short periodicity and long periodicity phases were identified for SCLLs containing phytosphingosines and sphingosine CERs, respectively. Furthermore, unsaturation in the CER acyl and FFA chains reduc...

Research paper thumbnail of Research Paper Information rich Descriptors for Predicting P-Glycoprotein Substrates and Non- substrates: A Binary-QSAR approach

A highly probabilistic binary quantitative structur e-activity relationship (binary-QSAR) model h... more A highly probabilistic binary quantitative structur e-activity relationship (binary-QSAR) model has been developed to predict substrates and non-su bstrates of P-glycoprotein (Pgp). A total of 123 compounds, classified as Pgp substrates/non-substra tes, on the basis of the efflux ratio from Pgp monolayer efflux assays were selected in this study . Binary-QSAR model is developed on training set of 99 diverse compound s (36 substrates and 63 non-substrates) using 12 inf ormation rich descriptors. Solubility, Lipinski violation score, partition coefficient, CYP2D6 enzyme substrate probability etc. were some of the important descriptors used in developin g binary-QSAR model. This model showed excellent overall prediction accuracy of 100% on substrates a nd non-substrates for training set of 99 compounds. Further, the leave-one-out cross-validated predicti on accuracy was 96.9% on substrates and non- substrates. When applied to the test set of 24 comp ounds (8 substrates and 16 non-subst...

Research paper thumbnail of Information rich Descriptors for Predicting P-Glycoprotein Substrates and Nonsubstrates: A Binary-QSAR approach

A highly probabilistic binary quantitative structure-activity relationship (binary-QSAR) model ha... more A highly probabilistic binary quantitative structure-activity relationship (binary-QSAR) model has been developed to predict substrates and non-substrates of P-glycoprotein (Pgp). A total of 123 compounds, classified as Pgp substrates/non-substrates, on the basis of the efflux ratio from Pgp monolayer efflux assays were selected in this study. Binary-QSAR model is developed on training set of 99 diverse compounds (36 substrates and 63 non-substrates) using 12 information rich descriptors. Solubility, Lipinski violation score, partition coefficient, CYP2D6 enzyme substrate probability etc. were some of the important descriptors used in developing binary-QSAR model. This model showed excellent overall prediction accuracy of 100% on substrates and non-substrates for training set of 99 compounds. Further, the leave-one-out cross-validated prediction accuracy was 96.9% on substrates and nonsubstrates. When applied to the test set of 24 compounds (8 substrates and 16 non-substrates), mode...

Research paper thumbnail of QSAR Models towards Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease

Quantitative Structure-Activity Relationships in Drug Design, Predictive Toxicology, and Risk Assessment, 2015

Research paper thumbnail of 2D-QSAR, Docking Studies, and In Silico ADMET Prediction of Polyphenolic Acetates as Substrates for Protein Acetyltransferase Function of Glutamine Synthetase of Mycobacterium tuberculosis

ISRN Structural Biology, 2013

A novel transacetylase (TAase) function of glutamine synthetase (GS) in bacterial species such as... more A novel transacetylase (TAase) function of glutamine synthetase (GS) in bacterial species such asMycobacterium smegmatisandMycobacterium tuberculosisH37Rv was established by us, termed as mycobacterial TAase (MTAase). Several polyphenolic acetates (PAs) were found to be substrates for MTAase by inhibiting certain receptor proteins such as glutathione S-transferase by way of acetylation. The present work describes the descriptor-based 2D-QSAR studies developed for a series of PA synthesized by us and evaluated for MTAase and antimycobacterial activity using stepwise multiple linear regression method with the kinetic constants and the minimum inhibitory constant (MIC) as the dependent variables, to address the fact that TAase activity was leading to the antimycobacterial activity. Further, blind docking methods using AutoDock were carried out to study the interaction of potent PA with the crystal structure ofM. tuberculosisGS. PAs were predicted to bindM. tuberculosisGS on the protein...

Research paper thumbnail of Dual Binding Site and Selective Acetylcholinesterase Inhibitors Derived from Integrated Pharmacophore Models and Sequential Virtual Screening

BioMed Research International, 2014

In this study, we have employedin silicomethodology combining double pharmacophore based screenin... more In this study, we have employedin silicomethodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer’s randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predi...

Research paper thumbnail of Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques

Bioorganic Medicinal Chemistry Letters, Feb 1, 2011

Research paper thumbnail of Molecular Docking Guided Comparative GFA, G/PLS, SVM and ANN Models of Structurally Diverse Dual Binding Site Acetylcholinesterase Inhibitors

Molecular …, 2011

Recently discovered 42 AChE inhibitors binding at the catalytic and peripheral anionic site were ... more Recently discovered 42 AChE inhibitors binding at the catalytic and peripheral anionic site were identified on the basis of molecular docking approach, and its comparative quantitative structure-activity relationship (QSAR) models were developed. These structurally diverse inhibitors were obtained by our previously reported high-throughput in vitro screening technique using 384-well plate's assay based on colorimetric method of Ellman. QSAR models were developed using (i) genetic function algorithm, (ii) genetic partial least squares, (iii) support vector machine and (iv) artificial neural network techniques. The QSAR model robustness and significance was critically assessed using different cross-validation techniques on test data set. The generated QSAR models using thermodynamic, electrotopological and electronic descriptors showed that nonlinear methods are more robust than linear methods, and provide insight into the structural features of compounds that are important for AChE inhibition.

Research paper thumbnail of Miniaturization and Validation of the Ellman's Reaction Based Acetylcholinesterase Inhibitory Assay into 384Well Plate Format and Screening of a Chemical Library

Combinatorial Chemistry & High Throughput Screening, 2010

Research paper thumbnail of Antiobesity and lipid lowering effects of Glycyrrhiza chalcones: Experimental and computational studies

Research paper thumbnail of Inhibition of acetylcholinesterase by coumarins: The case of coumarin 106

Pharmacological Research, 2008

Research paper thumbnail of 3D-pharmacophore model based virtual screening to identify dual-binding site and selective acetylcholinesterase inhibitors

Medicinal Chemistry Research

The formation of β-amyloid plaques in the brain is a key neurodegenerative event in Alzheimer’s d... more The formation of β-amyloid plaques in the brain is a key neurodegenerative event in Alzheimer’s disease (AD). Interestingly, research on acetylcholinesterase (AChE) enzyme has increased due to findings supporting this enzyme involvement in the β-amyloid peptide fibril formation during AD pathogenesis. In this investigation, chemical features based 3D pharmacophore models were developed from structurally diverse xanthostigmine derivatives, known inhibitors of AChE enzyme, using 3D-QSAR pharmacophore generation module in Discovery Studio2.5 (DS2.5). The constructed pharmacophore models for AChE inhibitors was further cross-validated using test set and Cat-Scramble methodology. The best quantitative pharmacophore model Hypo1, was used for screening the chemical databases of small compounds including Specs, NCI, and IBScreen, to identify the new compounds that are presumably able to act as dual-binding site AChE inhibitors. The screened virtual hits were then subjected to the Lipinski’s rule of five, blood–brain barrier (BBB), PSA, LogS, percent human oral absorption, and toxicity analysis. Finally, 32 compounds were identified as potential leads against AChE enzyme, showing good estimated activities and promising ADMET properties. Molecular docking of these compounds using FlexX software showed catalytic and peripheral anionic binding site interactions, so called dual binding of the AChE enzyme. Docking study was also performed on butyrylcholinesterase in order to understand the compound selectivity. This study may assist in the discovery and design of novel dual binding site and selective AChE inhibitors with potent inhibitory activity.

Research paper thumbnail of Ligand-based molecular design of 4-benzylpiperidinealkylureas and amides as CCR3 antagonists

Journal of Molecular Modeling, 2010

Asthma is an inflammatory disease of the lungs. Clinical studies suggest that eotaxin and chemoki... more Asthma is an inflammatory disease of the lungs. Clinical studies suggest that eotaxin and chemokine receptor-3 (CCR3) play a primary role in the recruitment of eosinophils in allergic asthma. Development of novel and potent CCR3 antagonists could provide a novel mechanism for inhibition of this recruitment process, thereby preventing asthma. With the intention of designing new ligands with enhanced inhibitor potencies against CCR3, a 3D-QSAR CoMFA study was carried out on 41 4-benzylpiperidinealkylureas and amide derivatives. The best statistics of the developed CoMFA model were r 2 = 0.960, \( r_{cv}^2 = 0.589 \) , n = 32 for the training set and \( r_{pred}^2 = 0.619 \) , n = 9 for the test set. The generated 3D-QSAR contribution maps shed some light on the effects of the substitution pattern related to CCR3 antagonist activity.

Research paper thumbnail of Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques

Bioorganic & Medicinal Chemistry Letters, 2011

Research paper thumbnail of Homology Modeling of Human α2A-Adrenoceptor

Nature Precedings, 2009

... doi :10.1038/npre.2009.4106.1. 0 votes. Homology Modeling of Human α 2A -Adrenoceptor. Jignes... more ... doi :10.1038/npre.2009.4106.1. 0 votes. Homology Modeling of Human α 2A -Adrenoceptor. Jignesh Patel 1 , Gourja G 1 , Vivek Kumar 1 , Yogesh Narkhede 1 , Shikhar Gupta 1 & C. Gopi Mohan 1. Correspondence: (Login to view email address). ...

Research paper thumbnail of In silico approach to discover multi-target-directed ligands for the treatment of Alzheimer's disease