Liliana Pacureanu - Academia.edu (original) (raw)
Papers by Liliana Pacureanu
Cross-target biochemical experiments demonstrated that some molecules display an ample spectrum o... more Cross-target biochemical experiments demonstrated that some molecules display an ample spectrum of biological activities which are therapeutically effective. In this regard we investigated the chemical space of the following targets GSK3, DPP IV and PPAR gamma since the DPP IV inhibitors, and PPAR gamma agonists are used to treat diabetes miellitus of type 2. Nevertheless, GSK-3 inhibitors have shown therapeutic potential for insulin resistant type-2 diabetes, the drug market does not register yet an inhibitor of GSK-2 for therapeutical use. The ChEMBL homo sapiens assay data for GSK-3, DPP IV and PPAR gamma were assembled into are database including 7599 compounds. GSK-3 assay comprise 2497 compounds, from which 1889 are unique divided into 428 chemotypes. DPP IV register 3482 compounds and 3026 were unique sharing 510 chemotypes. PPAR gamma incldes 1620 agonists from which 1333 are unique partitioned into 264 chemotypes. The chemical space of GSK3, DPP IV and PPAR gamma share 12 c...
We report herein an attempt to generate QSAR models for a large number of structurally diverse co... more We report herein an attempt to generate QSAR models for a large number of structurally diverse compounds (1078 compounds) whose affinities for cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were experimentally determined. Initially, individual QSAR models for COX-1 (M1) and COX-2 (M2) for biological activity were developed. A selectivity QSAR model, M3 was then developed using as dependent variable Y the differences in pIC50 values between COX-1 and COX-2. The statistical results for all three models showed a satisfactory to good statistical parameters where the values for squared correlation coefficient (coefficient of determination) for the training set are: M1: 0.872, M2: 0.797 respectively M3: 0.739. The predicted values of affinity in the case of all three models selected M1, M2 and respectively M3, are very good 84.88%, 91.12%, 79.59% which lead to very small diffrences between observed and predicted biological activity/selectivity (less than 0.5 logarithimic units)
The 24th International Electronic Conference on Synthetic Organic Chemistry, 2020
Glycogen synthase kinase-3 (GSK-3), one of the main tau kinases involved in a variety of cellular... more Glycogen synthase kinase-3 (GSK-3), one of the main tau kinases involved in a variety of cellular processes, has been evidenced as a promising target for Alzheimer's disease (AD) treatment. In recent years, great efforts have been made to discover new molecules with an enhanced profile that inhibit GSK-3 and display efficacy in AD treatment. SAR502250, a newly discovered selective GSK-3 inhibitor with AD therapeutic potential, represents a good alternative to design future specific inhibitors against this condition. SAR502250 was used as a query in a 3D similarity search on the SPECS database to select new natural compounds as possible GSK-3 inhibitors. According to ShapeTanimoto, TanimotoCombo, and ComboScore matrics, the first 10 SPECS natural compounds were selected and structurally analyzed. The ADME (Absorption, Distribution, Metabolism, and Excretion), physicochemical parameters, and toxicity-related risk profiles of the selected natural compounds were also investigated. The 3D similarity results in conjunction with pharmaceutical profiles revealed the potential use of natural compounds as GSK-3 inhibitors for Alzheimer's disease therapy.
Molecular Diversity, 2020
The main study's purpose is to detect novel natural products (NPs) that are potentially selective... more The main study's purpose is to detect novel natural products (NPs) that are potentially selective MAO-B inhibitors and, additionally, to computationally reposition the marketed drugs with a new therapeutic role for Parkinson's disease. To reach the goals, 3D similarity search, docking, ADMETox, and drug repurposing approaches were employed. Thus, an unbiased benchmarking dataset was built including selective and nonselective inhibitors for MAO-B compliant with both ligand-and structure-based virtual screening approaches. A retrospective and prospective mining scenario was applied to SPECS NP and DrugBank databases to detect novel scaffolds with potential benefits for Parkinson's disease patients. Out of the three best selected natural products, cardamomin showed excellently predicted drug-like properties, superior pharmacological profile, and specific interactions with MAO-B active site, indicating a potential selectivity over MAO-B. Two marketed drugs, fenamisal and monobenzone, were proposed as promising candidates repurposed for Parkinson's disease. The application of shape, physicochemical, and electrostatic similarity searches protocol emerged as a plausible solution to explore MAO-B inhibitors selectivity. This protocol might serve as a rewarding tool in early drug discovery and can be extended to other protein targets.
Chemistry Proceedings, 2020
Flavonoids, widely distributed in fruits, vegetables, and medicinal herbs, are compounds with mul... more Flavonoids, widely distributed in fruits, vegetables, and medicinal herbs, are compounds with multiple biological benefits to human health from anti-inflammatory, antioxidant, anticancer, antibacterial to antiviral activity. Coronavirus disease 2019 (COVID-19), a serious concern in the world today, is a respiratory tract disease involving moderate to severe symptoms of pneumonia, with a major incidence in older people and patients having chronic diseases. This emergency health situation led us to evaluate the possible use of natural products to prevent respiratory diseases. The present study aims to report the potential of four natural flavonoids, known to have anti-inflammatory and antiviral activity, as anti-SARS-CoV-2 through their binding on the 6YNQ protein receptor. Molecular docking study with the FRED program was chosen as an appropriate tool to analyze the interaction of natural flavonoids, quercetin, luteolin, galangin, and naringenin, with the SARS-CoV-2 main protease and...
Journal of Biomolecular Structure and Dynamics, 2020
Interaction signatures of drug candidates are characteristic to off-target (neutral) and antitarg... more Interaction signatures of drug candidates are characteristic to off-target (neutral) and antitarget (negative) effects, inferring reduced efficiency, side-effects and high attrition rate. Today's retroactive scaled-down virtual screening (VS) experiments relying on benchmarking datasets are extensively involved to assess ligand enrichment in the real-world problem. In recent years, unbiased benchmarking sets turned into a tremendous need to assist virtual screening methodologies for emerging drug targets. To date, the benchmarking datasets are quite limited, whereas glycogen synthase kinase-3 (GSK-3) is not included into directories of benchmarking datasets such as DUD-e, MUV, etc. Herein we introduced our in-house algorithm to build an unbiased benchmarking dataset, including highly selective, moderately selective and nonselective inhibitors for a significant therapeutic target-GSK-3, suitable for both ligand-based and structure-based VS approaches. These datasets are unbiased in terms of physico-chemical properties and topological descriptors, as resulted from mean(ROC-AUC) leave-one-out cross-validation (LOO CV). and additional 2D similarity search. Moreover, we investigated the gradual selectivity dataset by application of multiple 2D similarity coefficients and distances, 3D similarity and docking. Besides the resulted links between the enrichment of selective GSK-3 inhibitors and their chemical structures, a database of compounds and A c c e p t e d M a n u s c r i p t their 3D similarity signatures including cutoff thresholds for enhanced selectivity was generated. 2D similarity space analysis revealed that selectivity problem cannot be evaluated appropriately with 2D similarity searching alone. The current analysis provided useful, comprehensive insights, which may facilitate the knowledge-based identification of novel selective GSK-3 inhibitors.
Revista de Chimie, 2019
In this study pharmacophore modeling and molecular docking investigations have been performed on ... more In this study pharmacophore modeling and molecular docking investigations have been performed on pyrazolylaminoquinazoline derivatives, highly potent fibroblast growth factor receptor2 (FGFR2) inhibitors. The best pharmacophore hypotheses displaying five features (ADHRR.2051 and AADHR.798) were generated using a set of 28 compounds. The associated 3D atom-based quantitative structure � activity relationships (QSAR) models were statistically robust showing high correlation coefficients (R-squared = 0.981 / 0.982), and cross validation coefficients (Q-squared = 0.645 / 0.671). The R-Pearson values for the test set of 0.805 / 0.820 indicate that the models are robust and exhibit good predictive power. The interactions of pyrazolylaminoquinazoline with FGFR2 binding site revealed two hydrogen bonds with Ala567. The obtained pharmacophore, 3D atom-based QSAR models and binding features resulted from docking studies can help medicinal chemists to design new pyrazolylaminoquinazoline inhib...
Molecules, 2017
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used therapeutic agents that exhibit ... more Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used therapeutic agents that exhibit frequent and sometimes severe adverse effects, including gastrointestinal ulcerations and cardiovascular disorders. In an effort to obtain safer NSAIDs, we assessed the direct cyclooxygenase (COX) inhibition activity and we investigated the potential COX binding mode of some previously reported 2-(trimethoxyphenyl)-thiazoles. The in vitro COX inhibition assays were performed against ovine COX-1 and human recombinant COX-2. Molecular docking studies were performed to explain the possible interactions between the inhibitors and both COX isoforms binding pockets. Four of the tested compounds proved to be good inhibitors of both COX isoforms, but only compound A3 showed a good COX-2 selectivity index, similar to meloxicam. The plausible binding mode of compound A3 revealed hydrogen bond interactions with binding site key residues including Arg120, Tyr355, Ser530, Met522 and Trp387, whereas hydrophobic contacts were detected with Leu352, Val349, Leu359, Phe518, Gly526, and Ala527. Computationally predicted pharmacokinetic profile revealed A3 as lead candidate. The present data prove that the investigated compounds inhibit COX and thus confirm the previously reported in vivo anti-inflammatory screening results suggesting that A3 is a suitable candidate for further development as a NSAID.
Studia Universitatis Babes-Bolyai Chemia
The structure based retrospective virtual screening algorithm employed the docking engine FRED (F... more The structure based retrospective virtual screening algorithm employed the docking engine FRED (Fast Rigid Exhaustive Docking) to dock 74 inhibitors (4-aryl-3-anilino-maleimide derivatives) and 1778 decoy molecules into glycogen synthase kinase-3 β, GSK-3β, ATP-binding site (PDB code 1Q4L). The input database of 74 ligands was prepared following the OpenEye protocol by adding tautomers and ionization states, generating conformers, and performing charge corrections with AM1BCC option from QUACPAC software. The protein preparation has been carried out with Chimera software by deleting water molecules (except water near Thr 138), adding hydrogen and charges (AM1BCC). The energy component values of the scoring functions were subsequently submitted to PLS-DA (Projections in Latent Structures, Discriminant Analysis). The final PLS-DA result contains only the essential energy factors that describe most accurately the interactions in the ATP binding site. The results obtained are of better ...
Current Computer Aided-Drug Design, 2015
Xanthine-based molecules such as serine protease dipeptidyl peptidase 4 (DPP4) inhibitors are com... more Xanthine-based molecules such as serine protease dipeptidyl peptidase 4 (DPP4) inhibitors are compounds often used in improving glycemic control in type 2 diabetic patients and also used for their effects as mild stimulants and as bronchodilators, notably in treating asthma symptoms. Here, we aim to better understand the molecular features affecting activity of xanthine-based DPP4 inhibitors such as sitagliptin and related compounds and use these features to de novo predict improved sitagliptin derivatives. To this end, we performed a clinical study to examine the efficacy and safety of once-daily 100 mg oral sitagliptin as monotherapy in Romanian patients with type 2 diabetes. This study indicates that sitagliptin effectively decreases the glycemic level and provides very good glycemic equilibrium. To predict putative new drugs with identical pharmacological effects at lower dosages, we generate QSAR models based on compound series containing 35 DPP4 inhibitors. We establish that the physicochemical parameters critical for DPP4 inhibitory activity are: hydrophobicity described by the logarithm of the octanol/water partition coefficient, counts of rotatable bonds, hydrogen bond donor and acceptor atoms, and topological polar surface area. The predictive power of our QSAR models is indicated by significant values of statistical coefficients: cross-validated correlation q2 (0.77), fitted correlation coefficient r2 (0.85) and standard error of prediction (0.34). Based on the established QSAR equations, we propose and analyse 19 new sitagliptin derivatives with possibly improved pharmacological effect as DPP4 inhibitors.
ABSTRACT The structure based retrospective virtual screening algorithm employed the docking engin... more ABSTRACT The structure based retrospective virtual screening algorithm employed the docking engine FRED (Fast Rigid Exhaustive Docking) to dock 74 inhibitors (4-aryl-3-anilino-maleimide derivatives) and 1778 decoy molecules into glycogen synthase kinase-3 β, GSK-3β, ATP-binding site (PDB code 1Q4L). The input database of 74 ligands was prepared following the OpenEye protocol by adding tautomers and ionization states, generating conformers, and performing charge corrections with AM1BCC option from QUACPAC software. The protein preparation has been carried out with Chimera software by deleting water molecules (except water near Thr 138), adding hydrogen and charges (AM1BCC). The energy component values of the scoring functions were subsequently submitted to PLS-DA (Projections in Latent Structures, Discriminant Analysis). The final PLS-DA result contains only the essential energy factors that describe most accurately the interactions in the ATP binding site. The results obtained are of better quality than those obtained using the total scores provided by initial scoring functions in terms of AUC (Area Under Curve) 0.938 (chemgauss2 donor + screenscore rotatable bonds) with respect to 0.887 (chemgauss3). Moreover, the early enrichment of the PLS-DA term at 1% of the database is 13.514% while for Chemgauss 3 was only 8.108%.
Penicillins are valuable β -lactam antibiotics and useful starting materials for the preparation ... more Penicillins are valuable β -lactam antibiotics and useful starting materials for the preparation of semi-synthetic penicillins and cephalosporins. Penicillins are natural products of fungi such as Penicillium chrysogenum. The theoretical investigation of biological activity of penicillins has been studied systematically in the recent years and provided valuable insights. The diastereoisomer of (3S,5S,6S)-6-acetylamidopenicillanic acid has not yet been investigated. In the current investigation we used FRED (Fast Rigid Exhaustive Docking) to dock the conformers of (3S,5S,6S)-6-acetylamidopenicillanic acid into the crystal structure of Isopenicillin N Acyltransferase in complex with 6-aminopenicillanic acid (PDB code 2X1E). The influence of conformational expansion parameters and energy levels on the docking performances was investigated. The conformers of (3S,5S,6S)-6-acetylamidopenicillanic acid docked into the binding pocket suggested some biological activity on the basis of hydrogen bonding interactions (ARG 310, ASP121 similar to 2X1E ligand, and GLY311) and RMSD values.
revistadechimie.ro
... 4.PEAT, AJ, GARRIDO, D., BOUCHERON, JA, SCHWEIKER, SL, DICKERSON, SH, WILSON, JR, WANG TY, TH... more ... 4.PEAT, AJ, GARRIDO, D., BOUCHERON, JA, SCHWEIKER, SL, DICKERSON, SH, WILSON, JR, WANG TY, THOMSON, SA, Bioorg. ... R., LECLERC, S., ENDICOTT, J., NOBLE, M., LAWRIE, A., TUNNAH, P., LEOST, M., DAMIENS, E., MARIE, D., MARKO, D., NIEDERBERGER, E ...
Polymer Bulletin, 2001
Romanian Academy, Institute of Chemistry Timisoara, 24 Mihai Viteazul Bd., RO-1900 Timisoara, Rom... more Romanian Academy, Institute of Chemistry Timisoara, 24 Mihai Viteazul Bd., RO-1900 Timisoara, Romania e-mail: smail@acad-tim.utt.ro, Fax: +40-56/191824 * Department of Macromolecules, Polytechnic Institute of Iassy, 71 D. Mangeron Str., RO-6600 Iassy, ...
Phosphorus, Sulfur, and Silicon and the Related Elements, 2002
Phosphorus, Sulfur and Silicon, 2002, Vol. 177:20492050 Copyright C 2002 Taylor & Francis 10... more Phosphorus, Sulfur and Silicon, 2002, Vol. 177:20492050 Copyright C 2002 Taylor & Francis 1042-6507/02 $12.00 + .00 DOI: 10.1080/10426500290094242 ... Gheorghe Ilia, Smaranda Iliescu, Gheorghe Dehelean, Adriana Popa, Liliana Pacureanu, Lavinia Macarie, and ...
Monatshefte für Chemie - Chemical Monthly, 2012
ABSTRACT In silico screening algorithms are frequently included in drug discovery programs becaus... more ABSTRACT In silico screening algorithms are frequently included in drug discovery programs because a significant number of drug candidates have been detected through structure and ligand-based algorithms. In the current work 337 maleimide derivatives that are inhibitors and noninhibitors of GSK-3a/b were successfully investigated by means of a projection to latent structures discriminant analysis and hybrid docking. These models developed with Dragon (M1) and OpenEye (M2) descriptors are statistically robust (training set M1: RX 2 = 0.677, RY 2 = 0.976, QY 2 = 0.970; M2: RX 2 = 0.651, RY 2 = 0.835, QY 2 = 0.830) and suitably predictive according to Golbraikh–Tropsha external validation criteria (test set M1: R2 = 0.949; M2: R2 = 0.835). The models appropriately explained the structural differences between active and inactive compounds in terms of graph topology, substitutional pattern, and molecular flexibility, and predicted false negatives in PubChem assay 1650. The model M2 showed 73.88 % correct external prediction against 264 active maleimides downloaded from ChEMBL. An evaluation of the key interactions with GSK-3b binding site residues was simulated by hybrid docking. A new virtual screening methodology involving equation M2 and hybrid docking was applied to 9,042 maleimide derivatives extracted from PubChem. The model M2 predicted 1,327 active compounds that were subsequently docked into the GSK-3b ATP binding site. Finally 648 compounds were established as hits after the exclusion of previously detected active maleimides. The structural diversity of the new compounds is high demonstrating that the scaffold hopping ability of the current approach is noticeable.
Molecular Crystals and Liquid Crystals, 2004
ABSTRACT
Molecular Crystals and Liquid Crystals, 2004
Wastewaters generated by electroplating, Industry of Pigments, Tannins, etc. contain Cr(VI). The ... more Wastewaters generated by electroplating, Industry of Pigments, Tannins, etc. contain Cr(VI). The removal of Cr(VI) from wastewaters is necessary due to its toxicity; the admissible concentration being 10 ppm. This work studies quantitatively and qualitatively the possibility of treating ...
Journal of Molecular Modeling, 2007
The polarizabilities and the first and second hyperpolarizabilities of 219 conjugated organic com... more The polarizabilities and the first and second hyperpolarizabilities of 219 conjugated organic compounds are modeled by QSPR (quantitative structure activity relationship) based on a large pool of constitutional, topological, electronic and quantum chemical descriptors calculated by CODESSA Pro (comprehensive descriptors for structural and statistical analysis) derived solely from molecular structure. Multilinear models were developed using the BMLR (best multilinear regression) algorithm to relate the experimental (hyper)polarizabilities to their predicted values. The regression equations include AM1 (Austin model 1) calculated (hyper)polarizabilities together with the size, electrostatic and quantum chemical descriptors to compensate for the imprecision of the AM1 computational method. The results emphasize the main factors that influence (hyper)polarizability. All models were validated by the "leave-one-out" method and internal validations that confirmed the stability and good predictive ability.
Cross-target biochemical experiments demonstrated that some molecules display an ample spectrum o... more Cross-target biochemical experiments demonstrated that some molecules display an ample spectrum of biological activities which are therapeutically effective. In this regard we investigated the chemical space of the following targets GSK3, DPP IV and PPAR gamma since the DPP IV inhibitors, and PPAR gamma agonists are used to treat diabetes miellitus of type 2. Nevertheless, GSK-3 inhibitors have shown therapeutic potential for insulin resistant type-2 diabetes, the drug market does not register yet an inhibitor of GSK-2 for therapeutical use. The ChEMBL homo sapiens assay data for GSK-3, DPP IV and PPAR gamma were assembled into are database including 7599 compounds. GSK-3 assay comprise 2497 compounds, from which 1889 are unique divided into 428 chemotypes. DPP IV register 3482 compounds and 3026 were unique sharing 510 chemotypes. PPAR gamma incldes 1620 agonists from which 1333 are unique partitioned into 264 chemotypes. The chemical space of GSK3, DPP IV and PPAR gamma share 12 c...
We report herein an attempt to generate QSAR models for a large number of structurally diverse co... more We report herein an attempt to generate QSAR models for a large number of structurally diverse compounds (1078 compounds) whose affinities for cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were experimentally determined. Initially, individual QSAR models for COX-1 (M1) and COX-2 (M2) for biological activity were developed. A selectivity QSAR model, M3 was then developed using as dependent variable Y the differences in pIC50 values between COX-1 and COX-2. The statistical results for all three models showed a satisfactory to good statistical parameters where the values for squared correlation coefficient (coefficient of determination) for the training set are: M1: 0.872, M2: 0.797 respectively M3: 0.739. The predicted values of affinity in the case of all three models selected M1, M2 and respectively M3, are very good 84.88%, 91.12%, 79.59% which lead to very small diffrences between observed and predicted biological activity/selectivity (less than 0.5 logarithimic units)
The 24th International Electronic Conference on Synthetic Organic Chemistry, 2020
Glycogen synthase kinase-3 (GSK-3), one of the main tau kinases involved in a variety of cellular... more Glycogen synthase kinase-3 (GSK-3), one of the main tau kinases involved in a variety of cellular processes, has been evidenced as a promising target for Alzheimer's disease (AD) treatment. In recent years, great efforts have been made to discover new molecules with an enhanced profile that inhibit GSK-3 and display efficacy in AD treatment. SAR502250, a newly discovered selective GSK-3 inhibitor with AD therapeutic potential, represents a good alternative to design future specific inhibitors against this condition. SAR502250 was used as a query in a 3D similarity search on the SPECS database to select new natural compounds as possible GSK-3 inhibitors. According to ShapeTanimoto, TanimotoCombo, and ComboScore matrics, the first 10 SPECS natural compounds were selected and structurally analyzed. The ADME (Absorption, Distribution, Metabolism, and Excretion), physicochemical parameters, and toxicity-related risk profiles of the selected natural compounds were also investigated. The 3D similarity results in conjunction with pharmaceutical profiles revealed the potential use of natural compounds as GSK-3 inhibitors for Alzheimer's disease therapy.
Molecular Diversity, 2020
The main study's purpose is to detect novel natural products (NPs) that are potentially selective... more The main study's purpose is to detect novel natural products (NPs) that are potentially selective MAO-B inhibitors and, additionally, to computationally reposition the marketed drugs with a new therapeutic role for Parkinson's disease. To reach the goals, 3D similarity search, docking, ADMETox, and drug repurposing approaches were employed. Thus, an unbiased benchmarking dataset was built including selective and nonselective inhibitors for MAO-B compliant with both ligand-and structure-based virtual screening approaches. A retrospective and prospective mining scenario was applied to SPECS NP and DrugBank databases to detect novel scaffolds with potential benefits for Parkinson's disease patients. Out of the three best selected natural products, cardamomin showed excellently predicted drug-like properties, superior pharmacological profile, and specific interactions with MAO-B active site, indicating a potential selectivity over MAO-B. Two marketed drugs, fenamisal and monobenzone, were proposed as promising candidates repurposed for Parkinson's disease. The application of shape, physicochemical, and electrostatic similarity searches protocol emerged as a plausible solution to explore MAO-B inhibitors selectivity. This protocol might serve as a rewarding tool in early drug discovery and can be extended to other protein targets.
Chemistry Proceedings, 2020
Flavonoids, widely distributed in fruits, vegetables, and medicinal herbs, are compounds with mul... more Flavonoids, widely distributed in fruits, vegetables, and medicinal herbs, are compounds with multiple biological benefits to human health from anti-inflammatory, antioxidant, anticancer, antibacterial to antiviral activity. Coronavirus disease 2019 (COVID-19), a serious concern in the world today, is a respiratory tract disease involving moderate to severe symptoms of pneumonia, with a major incidence in older people and patients having chronic diseases. This emergency health situation led us to evaluate the possible use of natural products to prevent respiratory diseases. The present study aims to report the potential of four natural flavonoids, known to have anti-inflammatory and antiviral activity, as anti-SARS-CoV-2 through their binding on the 6YNQ protein receptor. Molecular docking study with the FRED program was chosen as an appropriate tool to analyze the interaction of natural flavonoids, quercetin, luteolin, galangin, and naringenin, with the SARS-CoV-2 main protease and...
Journal of Biomolecular Structure and Dynamics, 2020
Interaction signatures of drug candidates are characteristic to off-target (neutral) and antitarg... more Interaction signatures of drug candidates are characteristic to off-target (neutral) and antitarget (negative) effects, inferring reduced efficiency, side-effects and high attrition rate. Today's retroactive scaled-down virtual screening (VS) experiments relying on benchmarking datasets are extensively involved to assess ligand enrichment in the real-world problem. In recent years, unbiased benchmarking sets turned into a tremendous need to assist virtual screening methodologies for emerging drug targets. To date, the benchmarking datasets are quite limited, whereas glycogen synthase kinase-3 (GSK-3) is not included into directories of benchmarking datasets such as DUD-e, MUV, etc. Herein we introduced our in-house algorithm to build an unbiased benchmarking dataset, including highly selective, moderately selective and nonselective inhibitors for a significant therapeutic target-GSK-3, suitable for both ligand-based and structure-based VS approaches. These datasets are unbiased in terms of physico-chemical properties and topological descriptors, as resulted from mean(ROC-AUC) leave-one-out cross-validation (LOO CV). and additional 2D similarity search. Moreover, we investigated the gradual selectivity dataset by application of multiple 2D similarity coefficients and distances, 3D similarity and docking. Besides the resulted links between the enrichment of selective GSK-3 inhibitors and their chemical structures, a database of compounds and A c c e p t e d M a n u s c r i p t their 3D similarity signatures including cutoff thresholds for enhanced selectivity was generated. 2D similarity space analysis revealed that selectivity problem cannot be evaluated appropriately with 2D similarity searching alone. The current analysis provided useful, comprehensive insights, which may facilitate the knowledge-based identification of novel selective GSK-3 inhibitors.
Revista de Chimie, 2019
In this study pharmacophore modeling and molecular docking investigations have been performed on ... more In this study pharmacophore modeling and molecular docking investigations have been performed on pyrazolylaminoquinazoline derivatives, highly potent fibroblast growth factor receptor2 (FGFR2) inhibitors. The best pharmacophore hypotheses displaying five features (ADHRR.2051 and AADHR.798) were generated using a set of 28 compounds. The associated 3D atom-based quantitative structure � activity relationships (QSAR) models were statistically robust showing high correlation coefficients (R-squared = 0.981 / 0.982), and cross validation coefficients (Q-squared = 0.645 / 0.671). The R-Pearson values for the test set of 0.805 / 0.820 indicate that the models are robust and exhibit good predictive power. The interactions of pyrazolylaminoquinazoline with FGFR2 binding site revealed two hydrogen bonds with Ala567. The obtained pharmacophore, 3D atom-based QSAR models and binding features resulted from docking studies can help medicinal chemists to design new pyrazolylaminoquinazoline inhib...
Molecules, 2017
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used therapeutic agents that exhibit ... more Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used therapeutic agents that exhibit frequent and sometimes severe adverse effects, including gastrointestinal ulcerations and cardiovascular disorders. In an effort to obtain safer NSAIDs, we assessed the direct cyclooxygenase (COX) inhibition activity and we investigated the potential COX binding mode of some previously reported 2-(trimethoxyphenyl)-thiazoles. The in vitro COX inhibition assays were performed against ovine COX-1 and human recombinant COX-2. Molecular docking studies were performed to explain the possible interactions between the inhibitors and both COX isoforms binding pockets. Four of the tested compounds proved to be good inhibitors of both COX isoforms, but only compound A3 showed a good COX-2 selectivity index, similar to meloxicam. The plausible binding mode of compound A3 revealed hydrogen bond interactions with binding site key residues including Arg120, Tyr355, Ser530, Met522 and Trp387, whereas hydrophobic contacts were detected with Leu352, Val349, Leu359, Phe518, Gly526, and Ala527. Computationally predicted pharmacokinetic profile revealed A3 as lead candidate. The present data prove that the investigated compounds inhibit COX and thus confirm the previously reported in vivo anti-inflammatory screening results suggesting that A3 is a suitable candidate for further development as a NSAID.
Studia Universitatis Babes-Bolyai Chemia
The structure based retrospective virtual screening algorithm employed the docking engine FRED (F... more The structure based retrospective virtual screening algorithm employed the docking engine FRED (Fast Rigid Exhaustive Docking) to dock 74 inhibitors (4-aryl-3-anilino-maleimide derivatives) and 1778 decoy molecules into glycogen synthase kinase-3 β, GSK-3β, ATP-binding site (PDB code 1Q4L). The input database of 74 ligands was prepared following the OpenEye protocol by adding tautomers and ionization states, generating conformers, and performing charge corrections with AM1BCC option from QUACPAC software. The protein preparation has been carried out with Chimera software by deleting water molecules (except water near Thr 138), adding hydrogen and charges (AM1BCC). The energy component values of the scoring functions were subsequently submitted to PLS-DA (Projections in Latent Structures, Discriminant Analysis). The final PLS-DA result contains only the essential energy factors that describe most accurately the interactions in the ATP binding site. The results obtained are of better ...
Current Computer Aided-Drug Design, 2015
Xanthine-based molecules such as serine protease dipeptidyl peptidase 4 (DPP4) inhibitors are com... more Xanthine-based molecules such as serine protease dipeptidyl peptidase 4 (DPP4) inhibitors are compounds often used in improving glycemic control in type 2 diabetic patients and also used for their effects as mild stimulants and as bronchodilators, notably in treating asthma symptoms. Here, we aim to better understand the molecular features affecting activity of xanthine-based DPP4 inhibitors such as sitagliptin and related compounds and use these features to de novo predict improved sitagliptin derivatives. To this end, we performed a clinical study to examine the efficacy and safety of once-daily 100 mg oral sitagliptin as monotherapy in Romanian patients with type 2 diabetes. This study indicates that sitagliptin effectively decreases the glycemic level and provides very good glycemic equilibrium. To predict putative new drugs with identical pharmacological effects at lower dosages, we generate QSAR models based on compound series containing 35 DPP4 inhibitors. We establish that the physicochemical parameters critical for DPP4 inhibitory activity are: hydrophobicity described by the logarithm of the octanol/water partition coefficient, counts of rotatable bonds, hydrogen bond donor and acceptor atoms, and topological polar surface area. The predictive power of our QSAR models is indicated by significant values of statistical coefficients: cross-validated correlation q2 (0.77), fitted correlation coefficient r2 (0.85) and standard error of prediction (0.34). Based on the established QSAR equations, we propose and analyse 19 new sitagliptin derivatives with possibly improved pharmacological effect as DPP4 inhibitors.
ABSTRACT The structure based retrospective virtual screening algorithm employed the docking engin... more ABSTRACT The structure based retrospective virtual screening algorithm employed the docking engine FRED (Fast Rigid Exhaustive Docking) to dock 74 inhibitors (4-aryl-3-anilino-maleimide derivatives) and 1778 decoy molecules into glycogen synthase kinase-3 β, GSK-3β, ATP-binding site (PDB code 1Q4L). The input database of 74 ligands was prepared following the OpenEye protocol by adding tautomers and ionization states, generating conformers, and performing charge corrections with AM1BCC option from QUACPAC software. The protein preparation has been carried out with Chimera software by deleting water molecules (except water near Thr 138), adding hydrogen and charges (AM1BCC). The energy component values of the scoring functions were subsequently submitted to PLS-DA (Projections in Latent Structures, Discriminant Analysis). The final PLS-DA result contains only the essential energy factors that describe most accurately the interactions in the ATP binding site. The results obtained are of better quality than those obtained using the total scores provided by initial scoring functions in terms of AUC (Area Under Curve) 0.938 (chemgauss2 donor + screenscore rotatable bonds) with respect to 0.887 (chemgauss3). Moreover, the early enrichment of the PLS-DA term at 1% of the database is 13.514% while for Chemgauss 3 was only 8.108%.
Penicillins are valuable β -lactam antibiotics and useful starting materials for the preparation ... more Penicillins are valuable β -lactam antibiotics and useful starting materials for the preparation of semi-synthetic penicillins and cephalosporins. Penicillins are natural products of fungi such as Penicillium chrysogenum. The theoretical investigation of biological activity of penicillins has been studied systematically in the recent years and provided valuable insights. The diastereoisomer of (3S,5S,6S)-6-acetylamidopenicillanic acid has not yet been investigated. In the current investigation we used FRED (Fast Rigid Exhaustive Docking) to dock the conformers of (3S,5S,6S)-6-acetylamidopenicillanic acid into the crystal structure of Isopenicillin N Acyltransferase in complex with 6-aminopenicillanic acid (PDB code 2X1E). The influence of conformational expansion parameters and energy levels on the docking performances was investigated. The conformers of (3S,5S,6S)-6-acetylamidopenicillanic acid docked into the binding pocket suggested some biological activity on the basis of hydrogen bonding interactions (ARG 310, ASP121 similar to 2X1E ligand, and GLY311) and RMSD values.
revistadechimie.ro
... 4.PEAT, AJ, GARRIDO, D., BOUCHERON, JA, SCHWEIKER, SL, DICKERSON, SH, WILSON, JR, WANG TY, TH... more ... 4.PEAT, AJ, GARRIDO, D., BOUCHERON, JA, SCHWEIKER, SL, DICKERSON, SH, WILSON, JR, WANG TY, THOMSON, SA, Bioorg. ... R., LECLERC, S., ENDICOTT, J., NOBLE, M., LAWRIE, A., TUNNAH, P., LEOST, M., DAMIENS, E., MARIE, D., MARKO, D., NIEDERBERGER, E ...
Polymer Bulletin, 2001
Romanian Academy, Institute of Chemistry Timisoara, 24 Mihai Viteazul Bd., RO-1900 Timisoara, Rom... more Romanian Academy, Institute of Chemistry Timisoara, 24 Mihai Viteazul Bd., RO-1900 Timisoara, Romania e-mail: smail@acad-tim.utt.ro, Fax: +40-56/191824 * Department of Macromolecules, Polytechnic Institute of Iassy, 71 D. Mangeron Str., RO-6600 Iassy, ...
Phosphorus, Sulfur, and Silicon and the Related Elements, 2002
Phosphorus, Sulfur and Silicon, 2002, Vol. 177:20492050 Copyright C 2002 Taylor & Francis 10... more Phosphorus, Sulfur and Silicon, 2002, Vol. 177:20492050 Copyright C 2002 Taylor & Francis 1042-6507/02 $12.00 + .00 DOI: 10.1080/10426500290094242 ... Gheorghe Ilia, Smaranda Iliescu, Gheorghe Dehelean, Adriana Popa, Liliana Pacureanu, Lavinia Macarie, and ...
Monatshefte für Chemie - Chemical Monthly, 2012
ABSTRACT In silico screening algorithms are frequently included in drug discovery programs becaus... more ABSTRACT In silico screening algorithms are frequently included in drug discovery programs because a significant number of drug candidates have been detected through structure and ligand-based algorithms. In the current work 337 maleimide derivatives that are inhibitors and noninhibitors of GSK-3a/b were successfully investigated by means of a projection to latent structures discriminant analysis and hybrid docking. These models developed with Dragon (M1) and OpenEye (M2) descriptors are statistically robust (training set M1: RX 2 = 0.677, RY 2 = 0.976, QY 2 = 0.970; M2: RX 2 = 0.651, RY 2 = 0.835, QY 2 = 0.830) and suitably predictive according to Golbraikh–Tropsha external validation criteria (test set M1: R2 = 0.949; M2: R2 = 0.835). The models appropriately explained the structural differences between active and inactive compounds in terms of graph topology, substitutional pattern, and molecular flexibility, and predicted false negatives in PubChem assay 1650. The model M2 showed 73.88 % correct external prediction against 264 active maleimides downloaded from ChEMBL. An evaluation of the key interactions with GSK-3b binding site residues was simulated by hybrid docking. A new virtual screening methodology involving equation M2 and hybrid docking was applied to 9,042 maleimide derivatives extracted from PubChem. The model M2 predicted 1,327 active compounds that were subsequently docked into the GSK-3b ATP binding site. Finally 648 compounds were established as hits after the exclusion of previously detected active maleimides. The structural diversity of the new compounds is high demonstrating that the scaffold hopping ability of the current approach is noticeable.
Molecular Crystals and Liquid Crystals, 2004
ABSTRACT
Molecular Crystals and Liquid Crystals, 2004
Wastewaters generated by electroplating, Industry of Pigments, Tannins, etc. contain Cr(VI). The ... more Wastewaters generated by electroplating, Industry of Pigments, Tannins, etc. contain Cr(VI). The removal of Cr(VI) from wastewaters is necessary due to its toxicity; the admissible concentration being 10 ppm. This work studies quantitatively and qualitatively the possibility of treating ...
Journal of Molecular Modeling, 2007
The polarizabilities and the first and second hyperpolarizabilities of 219 conjugated organic com... more The polarizabilities and the first and second hyperpolarizabilities of 219 conjugated organic compounds are modeled by QSPR (quantitative structure activity relationship) based on a large pool of constitutional, topological, electronic and quantum chemical descriptors calculated by CODESSA Pro (comprehensive descriptors for structural and statistical analysis) derived solely from molecular structure. Multilinear models were developed using the BMLR (best multilinear regression) algorithm to relate the experimental (hyper)polarizabilities to their predicted values. The regression equations include AM1 (Austin model 1) calculated (hyper)polarizabilities together with the size, electrostatic and quantum chemical descriptors to compensate for the imprecision of the AM1 computational method. The results emphasize the main factors that influence (hyper)polarizability. All models were validated by the "leave-one-out" method and internal validations that confirmed the stability and good predictive ability.