Girinath G. Pillai | University of Tartu (original) (raw)
Papers by Girinath G. Pillai
Scientific reports, Jan 19, 2017
A novel series of hybrid analogues of monastrol-1,3,5-triazine were designed and developed via on... more A novel series of hybrid analogues of monastrol-1,3,5-triazine were designed and developed via one-pot synthesis using Bi(NO3)3 as a catalyst. Entire compounds were evaluated for their anticancer activity against HeLa (cervical cancer), MCF-7 (breast cancer), HL-60 (Human promyelocytic leukemia), HepG2 (Hepatocellular carcinoma) and MCF 12A (normal epithelial breast cell line) using MTT assay, where they showed highest inhibitory activity against MCF-7. The molecules were also found to be non-toxic to MCF 12A cells. These molecules showed considerable inhibitory percentage against Epidermal Growth Factor Receptor tyrosine kinase (EGFR-TK), in in-vitro assay. Molecular docking study was carried out on the analogs and reference compound (Erlotinib) into the ATP binding site of EGFR-TK domain (PDB ID:1M17) to elucidate vital structural residues necessary for bioactivity. The effect of most active compound 7l was also estimated in-vivo in DMBA induced mammary tumor in female Sprague-Daw...
Org. Biomol. Chem., 2016
An efficient methodology for cysteine-free ligation at a tryptophan (Trp) site is described. A ch... more An efficient methodology for cysteine-free ligation at a tryptophan (Trp) site is described. A chemically active scaffold, β-hydroxy-α-azidotryptophan, has been synthesized and explored towards the synthesis of a series of β-hydroxytryptophan appended native peptides in good yields via one-pot reductive traceless ligation of β-O-peptidyl-α-azidotryptophan involving an O → N peptidyl transfer strategy. Pre-organized conformational analysis and reaction energy pathway based theoretical studies further supported the experimental findings on the chemical structure stability of ligated products.
The Journal of pharmacology and experimental therapeutics, Jun 30, 2016
GABA-A receptors meet all the pharmacological requirements necessary to be considered important t... more GABA-A receptors meet all the pharmacological requirements necessary to be considered important targets for the action of general anesthetic agents in the mammalian brain. In the following patch-clamp study, the relative modulatory effects of 2,6 dimethylcyclohexanol diastereomers were investigated on human γ-aminobutyric acid type A (GABA-A, α1β3γ2s) receptor currents stably expressed in human embryonic kidney cells. Cis,cis; trans,trans; and cis,trans isomers were isolated from commercially available 2,6 dimethylcyclohexanol and were tested for positive modulation of sub-maximal GABA responses. For example, the addition of 30 μM cis,cis isomer resulted in ~2-3 fold enhancement of the EC20 GABA current. Co-applications of 30 μM 2,6-dimethylcyclohexanol isomers produced a range of positive enhancements of control GABA responses with a rank order for positive modulation: cis,cis > trans,trans ≥ mixture of isomers > cis,trans isomer. In molecular modeling studies, the three cycl...
Medicinal chemistry (Shariqah (United Arab Emirates)), Jan 5, 2015
Chemically diverse scaffold set of HIV-1 Reverse Transcriptase Inhibitors (HIV-1 RTI) was subject... more Chemically diverse scaffold set of HIV-1 Reverse Transcriptase Inhibitors (HIV-1 RTI) was subjected to optimum oriented QSAR with large descriptor space. We generated four-parameter QSAR model based on 111 data points, which provides an optimum prediction of HIV-1 RTI for overall 367 experimentally measured compounds. The robustness of the model is demonstrated by its statistical validation and by the prediction of HIV-1 inhibition activity. A statistically significant QSAR model describing the anti-viral properties of NNRTIs (Ntraining = 111, R2 = 0.85, F=145.55, Q2lmo = 0.84) was obtained. Finally, 3 new hit compounds that met the pharmacophore constraints, similarity and had good predicted pIC50 values from in-silico virtual screening process were employed to analyze the binding ability by molecular modelling studies on HIV-1 RT protein targets.
Chemical research in toxicology, Jan 18, 2015
Many chemicals can induce skin sensitization, and there is a pressing need for non-animal methods... more Many chemicals can induce skin sensitization, and there is a pressing need for non-animal methods to give a quantitative indication of potency. Using two large published data-sets of skin sensitizers, we have allocated each sensitizing chemical to one of ten mechanistic categories, and then developed good QSAR models for the seven categories with a sufficient number of chemicals to allow modeling. Both internal and external validation checks showed that each model had good predictivity.
Org. Biomol. Chem., 2015
QSAR study describes the anti-neoplastic spiro-alkaloids with relevant molecular descriptors usin... more QSAR study describes the anti-neoplastic spiro-alkaloids with relevant molecular descriptors using CODESSA III software.
Journal of Peptide Science, 2014
Natural tetrapeptide Goralatide inhibits primitive hematopoietic cell proliferation but reported ... more Natural tetrapeptide Goralatide inhibits primitive hematopoietic cell proliferation but reported to be rather unstable in solution (half-life 4.5 min). In this work, we report the synthesis of an aminoxy analog of Goralatide. Aminoxy moiety is expected to provide increased stability and bioavailability of the Goralatide analog.
Chemistry (Weinheim an der Bergstrasse, Germany), Jan 23, 2014
Chemical ligations to form native peptides from N→N acyl migrations in Trp-containing peptides vi... more Chemical ligations to form native peptides from N→N acyl migrations in Trp-containing peptides via 10- to 18-membered cyclic transition states are described. In this study, a statistical, predictive model that uses an extensive synthetic and computational approach to rationalize the chemical ligation is reported. N→N acyl migrations that form longer native peptides without the use of Cys/Ser/Tyr residues or an auxiliary group at the ligation site were achieved. The feasibility of these traceless chemical ligations is supported by the N-C bond distance in N-acyl isopeptides. The intramolecular nature of the chemical ligations is justified by using competitive experiments and theoretical calculations.
Organic & biomolecular chemistry, Jan 10, 2015
Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole ... more Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole chemistry. Microbiological testing of the synthesized compounds revealed an exceptionally high activity against Candida albicans with a minimum inhibitory concentration (MIC) two orders of magnitude lower than the MIC of the antifungal reference drug amphotericin B. A strikingly high activity was also observed against three Gram-negative bacterial strains (Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris), two of which are known human pathogens. Thus the discovered chemotype is a potential polypharmacological agent. The toxicity against mammalian tumor cells was found to be low, as demonstrated in five different human cell lines (HeLa, cervical; PC-3, prostate; MCF-7, breast; HepG2, liver; and HCT-116, colon). The internal consistency of the experimental data was studied using 3D-pharmacophore and 2D-QSAR.
Current Topics in Medicinal Chemistry, 2014
Machine learning (ML) computational methods for predicting compounds with pharmacological activit... more Machine learning (ML) computational methods for predicting compounds with pharmacological activity, specific pharmacodynamic and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties are being increasingly applied in drug discovery and evaluation. Recently, machine learning techniques such as artificial neural networks, support vector machines and genetic programming have been explored for predicting inhibitors, antagonists, blockers, agonists, activators and substrates of proteins related to specific therapeutic targets. These methods are particularly useful for screening compound libraries of diverse chemical structures, "noisy" and high-dimensional data to complement QSAR methods, and in cases of unavailable receptor 3D structure to complement structure-based methods. A variety of studies have demonstrated the potential of machine-learning methods for predicting compounds as potential drug candidates. The present review is intended to give an overview of the strategies and current progress in using machine learning methods for drug design and the potential of the respective model development tools. We also regard a number of applications of the machine learning algorithms based on common classes of diseases.
ABSTRACT Enantiopure cyclic peptidomimetic antimicrobials compds. that contain S- cysteine ester ... more ABSTRACT Enantiopure cyclic peptidomimetic antimicrobials compds. that contain S- cysteine ester units and at least one pyridine unit within the macrocyclic ring have been prepd. that show exceptional antifungal and antibacterial activity. These 17- or 18- membered macrocyclic compds. display MIC values as antifungal agents as low as 7.5 nm /mL and MIC values as antibacterial agents as low as 0.2 nm /mL. All the macrocyclic peptidomimetic compds. are isolated as cryst. solids in good yield
Current computer-aided drug design, Jan 26, 2014
Structure-activity relations in a data set of HPV6-E1 helicase ATPase inhibitors were investigate... more Structure-activity relations in a data set of HPV6-E1 helicase ATPase inhibitors were investigated based on two different sets of descriptors. Statistically significant four parameter Quantitative Structure-Activity Relationships (QSAR) models were constructed and validated in both cases (R2=0.849; R2cv=0.811; F=52.20; s2=0.25; N=42). A Fragment based QSAR (FQSAR) approach was applied for developing a fragment-QSAR equation, which enabled the construction of virtual structures for novel ATPase inhibitors with desired or pre-defined activity.
Journal of Chemical Information and Modeling, 2014
A diverse training set composed of 76 in-house synthesized and 61 collected from the literature, ... more A diverse training set composed of 76 in-house synthesized and 61 collected from the literature, was subjected to Molecular Field Topology Analysis. This resulted in a high quality quantitative structure-activity relationships model (R 2 = 0.932, Q 2 = 0.809) which was used for the topological functional core identification and prediction of vasodilatory activity of 19 novel pyridinecarbonitriles, which turned out to be active in experimental bioassay.
European Journal of Medicinal Chemistry, 2014
Chemistry - A European Journal, 2014
European Journal of Organic Chemistry, 2015
European Journal of Medicinal Chemistry, 2014
Fourteen new N-acetylated and non-acetylated pyrazoline derivatives were synthesized by reacting ... more Fourteen new N-acetylated and non-acetylated pyrazoline derivatives were synthesized by reacting chalcones with hydrazine in the presence of absolute ethanol however reaction was carried out in the presence of glacial acetic acid to afford N-acetylated pyrazolines. The chemical structures of the synthesized pyrazolines were confirmed by FTIR, 1 HNMR, 13 CNMR and mass spectroscopic data. were screened for antibacterial activity against ten bacterial strains using seven Gram-positive and three Gram-negative bacteria and antifungal activity against Aspergillus Flavus, Aspergillus Niger and Aspergillus pterus. found to exhibit good to excellent antimicrobial activities compared to the Levofloxacin and fluconazole used as standard drugs.
European Journal of Organic Chemistry, 2015
Tetrahedron Letters, 2016
Scientific reports, Jan 19, 2017
A novel series of hybrid analogues of monastrol-1,3,5-triazine were designed and developed via on... more A novel series of hybrid analogues of monastrol-1,3,5-triazine were designed and developed via one-pot synthesis using Bi(NO3)3 as a catalyst. Entire compounds were evaluated for their anticancer activity against HeLa (cervical cancer), MCF-7 (breast cancer), HL-60 (Human promyelocytic leukemia), HepG2 (Hepatocellular carcinoma) and MCF 12A (normal epithelial breast cell line) using MTT assay, where they showed highest inhibitory activity against MCF-7. The molecules were also found to be non-toxic to MCF 12A cells. These molecules showed considerable inhibitory percentage against Epidermal Growth Factor Receptor tyrosine kinase (EGFR-TK), in in-vitro assay. Molecular docking study was carried out on the analogs and reference compound (Erlotinib) into the ATP binding site of EGFR-TK domain (PDB ID:1M17) to elucidate vital structural residues necessary for bioactivity. The effect of most active compound 7l was also estimated in-vivo in DMBA induced mammary tumor in female Sprague-Daw...
Org. Biomol. Chem., 2016
An efficient methodology for cysteine-free ligation at a tryptophan (Trp) site is described. A ch... more An efficient methodology for cysteine-free ligation at a tryptophan (Trp) site is described. A chemically active scaffold, β-hydroxy-α-azidotryptophan, has been synthesized and explored towards the synthesis of a series of β-hydroxytryptophan appended native peptides in good yields via one-pot reductive traceless ligation of β-O-peptidyl-α-azidotryptophan involving an O → N peptidyl transfer strategy. Pre-organized conformational analysis and reaction energy pathway based theoretical studies further supported the experimental findings on the chemical structure stability of ligated products.
The Journal of pharmacology and experimental therapeutics, Jun 30, 2016
GABA-A receptors meet all the pharmacological requirements necessary to be considered important t... more GABA-A receptors meet all the pharmacological requirements necessary to be considered important targets for the action of general anesthetic agents in the mammalian brain. In the following patch-clamp study, the relative modulatory effects of 2,6 dimethylcyclohexanol diastereomers were investigated on human γ-aminobutyric acid type A (GABA-A, α1β3γ2s) receptor currents stably expressed in human embryonic kidney cells. Cis,cis; trans,trans; and cis,trans isomers were isolated from commercially available 2,6 dimethylcyclohexanol and were tested for positive modulation of sub-maximal GABA responses. For example, the addition of 30 μM cis,cis isomer resulted in ~2-3 fold enhancement of the EC20 GABA current. Co-applications of 30 μM 2,6-dimethylcyclohexanol isomers produced a range of positive enhancements of control GABA responses with a rank order for positive modulation: cis,cis > trans,trans ≥ mixture of isomers > cis,trans isomer. In molecular modeling studies, the three cycl...
Medicinal chemistry (Shariqah (United Arab Emirates)), Jan 5, 2015
Chemically diverse scaffold set of HIV-1 Reverse Transcriptase Inhibitors (HIV-1 RTI) was subject... more Chemically diverse scaffold set of HIV-1 Reverse Transcriptase Inhibitors (HIV-1 RTI) was subjected to optimum oriented QSAR with large descriptor space. We generated four-parameter QSAR model based on 111 data points, which provides an optimum prediction of HIV-1 RTI for overall 367 experimentally measured compounds. The robustness of the model is demonstrated by its statistical validation and by the prediction of HIV-1 inhibition activity. A statistically significant QSAR model describing the anti-viral properties of NNRTIs (Ntraining = 111, R2 = 0.85, F=145.55, Q2lmo = 0.84) was obtained. Finally, 3 new hit compounds that met the pharmacophore constraints, similarity and had good predicted pIC50 values from in-silico virtual screening process were employed to analyze the binding ability by molecular modelling studies on HIV-1 RT protein targets.
Chemical research in toxicology, Jan 18, 2015
Many chemicals can induce skin sensitization, and there is a pressing need for non-animal methods... more Many chemicals can induce skin sensitization, and there is a pressing need for non-animal methods to give a quantitative indication of potency. Using two large published data-sets of skin sensitizers, we have allocated each sensitizing chemical to one of ten mechanistic categories, and then developed good QSAR models for the seven categories with a sufficient number of chemicals to allow modeling. Both internal and external validation checks showed that each model had good predictivity.
Org. Biomol. Chem., 2015
QSAR study describes the anti-neoplastic spiro-alkaloids with relevant molecular descriptors usin... more QSAR study describes the anti-neoplastic spiro-alkaloids with relevant molecular descriptors using CODESSA III software.
Journal of Peptide Science, 2014
Natural tetrapeptide Goralatide inhibits primitive hematopoietic cell proliferation but reported ... more Natural tetrapeptide Goralatide inhibits primitive hematopoietic cell proliferation but reported to be rather unstable in solution (half-life 4.5 min). In this work, we report the synthesis of an aminoxy analog of Goralatide. Aminoxy moiety is expected to provide increased stability and bioavailability of the Goralatide analog.
Chemistry (Weinheim an der Bergstrasse, Germany), Jan 23, 2014
Chemical ligations to form native peptides from N→N acyl migrations in Trp-containing peptides vi... more Chemical ligations to form native peptides from N→N acyl migrations in Trp-containing peptides via 10- to 18-membered cyclic transition states are described. In this study, a statistical, predictive model that uses an extensive synthetic and computational approach to rationalize the chemical ligation is reported. N→N acyl migrations that form longer native peptides without the use of Cys/Ser/Tyr residues or an auxiliary group at the ligation site were achieved. The feasibility of these traceless chemical ligations is supported by the N-C bond distance in N-acyl isopeptides. The intramolecular nature of the chemical ligations is justified by using competitive experiments and theoretical calculations.
Organic & biomolecular chemistry, Jan 10, 2015
Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole ... more Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole chemistry. Microbiological testing of the synthesized compounds revealed an exceptionally high activity against Candida albicans with a minimum inhibitory concentration (MIC) two orders of magnitude lower than the MIC of the antifungal reference drug amphotericin B. A strikingly high activity was also observed against three Gram-negative bacterial strains (Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris), two of which are known human pathogens. Thus the discovered chemotype is a potential polypharmacological agent. The toxicity against mammalian tumor cells was found to be low, as demonstrated in five different human cell lines (HeLa, cervical; PC-3, prostate; MCF-7, breast; HepG2, liver; and HCT-116, colon). The internal consistency of the experimental data was studied using 3D-pharmacophore and 2D-QSAR.
Current Topics in Medicinal Chemistry, 2014
Machine learning (ML) computational methods for predicting compounds with pharmacological activit... more Machine learning (ML) computational methods for predicting compounds with pharmacological activity, specific pharmacodynamic and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties are being increasingly applied in drug discovery and evaluation. Recently, machine learning techniques such as artificial neural networks, support vector machines and genetic programming have been explored for predicting inhibitors, antagonists, blockers, agonists, activators and substrates of proteins related to specific therapeutic targets. These methods are particularly useful for screening compound libraries of diverse chemical structures, "noisy" and high-dimensional data to complement QSAR methods, and in cases of unavailable receptor 3D structure to complement structure-based methods. A variety of studies have demonstrated the potential of machine-learning methods for predicting compounds as potential drug candidates. The present review is intended to give an overview of the strategies and current progress in using machine learning methods for drug design and the potential of the respective model development tools. We also regard a number of applications of the machine learning algorithms based on common classes of diseases.
ABSTRACT Enantiopure cyclic peptidomimetic antimicrobials compds. that contain S- cysteine ester ... more ABSTRACT Enantiopure cyclic peptidomimetic antimicrobials compds. that contain S- cysteine ester units and at least one pyridine unit within the macrocyclic ring have been prepd. that show exceptional antifungal and antibacterial activity. These 17- or 18- membered macrocyclic compds. display MIC values as antifungal agents as low as 7.5 nm /mL and MIC values as antibacterial agents as low as 0.2 nm /mL. All the macrocyclic peptidomimetic compds. are isolated as cryst. solids in good yield
Current computer-aided drug design, Jan 26, 2014
Structure-activity relations in a data set of HPV6-E1 helicase ATPase inhibitors were investigate... more Structure-activity relations in a data set of HPV6-E1 helicase ATPase inhibitors were investigated based on two different sets of descriptors. Statistically significant four parameter Quantitative Structure-Activity Relationships (QSAR) models were constructed and validated in both cases (R2=0.849; R2cv=0.811; F=52.20; s2=0.25; N=42). A Fragment based QSAR (FQSAR) approach was applied for developing a fragment-QSAR equation, which enabled the construction of virtual structures for novel ATPase inhibitors with desired or pre-defined activity.
Journal of Chemical Information and Modeling, 2014
A diverse training set composed of 76 in-house synthesized and 61 collected from the literature, ... more A diverse training set composed of 76 in-house synthesized and 61 collected from the literature, was subjected to Molecular Field Topology Analysis. This resulted in a high quality quantitative structure-activity relationships model (R 2 = 0.932, Q 2 = 0.809) which was used for the topological functional core identification and prediction of vasodilatory activity of 19 novel pyridinecarbonitriles, which turned out to be active in experimental bioassay.
European Journal of Medicinal Chemistry, 2014
Chemistry - A European Journal, 2014
European Journal of Organic Chemistry, 2015
European Journal of Medicinal Chemistry, 2014
Fourteen new N-acetylated and non-acetylated pyrazoline derivatives were synthesized by reacting ... more Fourteen new N-acetylated and non-acetylated pyrazoline derivatives were synthesized by reacting chalcones with hydrazine in the presence of absolute ethanol however reaction was carried out in the presence of glacial acetic acid to afford N-acetylated pyrazolines. The chemical structures of the synthesized pyrazolines were confirmed by FTIR, 1 HNMR, 13 CNMR and mass spectroscopic data. were screened for antibacterial activity against ten bacterial strains using seven Gram-positive and three Gram-negative bacteria and antifungal activity against Aspergillus Flavus, Aspergillus Niger and Aspergillus pterus. found to exhibit good to excellent antimicrobial activities compared to the Levofloxacin and fluconazole used as standard drugs.
European Journal of Organic Chemistry, 2015
Tetrahedron Letters, 2016