Publications (61)172.27 Total impact
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Article: Predictive QSAR models development and validation for human ether-a-go-go related gene (hERG) blockers using newer tools.
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ABSTRACT: Abstract In the present computational analysis, pharmacophore-based active conformer selection method was used to derive active conformers for the physicochemical descriptors calculation. The significant regression models were validated using different validation methods, which provided significant Q(2) values. The distance-based approaches were also used to analyze the discriminant property of the molecules contributed in the models. The Mahalanobis distance (MD) values obtained from these studies revealed that the compounds with very high and very low acting human ether-a-go-go-related gene blockers possessed high MD values, while the predicted activity of those compounds exhibited less residual errors. The results obtained in the studies suggest that the distance-based approaches can be used to validate the quantitative structure-activity relationship models significantly. The descriptors contributed in the models explain that the flexibility of the bonds connected to the aromatic rings or non-polar region of the molecules make π-π interaction with the aromatic residues of the protein.Journal of Enzyme Inhibition and Medicinal Chemistry 04/2013; · 1.62 Impact Factor -
Article: Molecular dynamics studies on both bound and unbound renin protease.
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ABSTRACT: The aspartic protease renin (REN) catalyses the rate-limiting step in the Renin-Angiotensin-Aldosterone System (RAAS), which regulates cardiovascular and renal homoeostasis in living organisms. Renin blockage is therefore an attractive therapeutic strategy for the treatment of hypertension. Herein, computational approaches were used to provide a structural characterization of the binding site, flap opening and dynamic rearrangements of REN in the key conserved residues and water molecules, with the binding of a dodecapeptide substrate or different inhibitors. All these structural insights during catalysis may assist future studies in developing novel strategies for REN inactivation. Our molecular dynamics simulations of several unbound-REN and bound-REN systems indicate similar flexible-segments plasticity with larger fluctuations in those belonging to the C-domain (exposed to the solvent). These segments are thought to assist the flap opening and closure to allow the binding of the substrate and catalytic water molecules. The unbound-REN simulation suggests that the flap can acquire three different conformations: closed, semi-open and open. Our results indicate that the semi-open conformation is already sufficient and appropriate for the binding of the angiotensinogen (Ang) tail, thus contributing to the high specificity of REN, and that both semi-open and open flap conformations are present in free and complexed enzymes. We additionally observed that the Tyr75-Trp39 H-bond has an important role in assisting flap movement, and we highlight several conserved water molecules and amino acids that are essential for the proper catalytic activity of REN.Journal of biomolecular structure & dynamics 03/2013; · 4.99 Impact Factor -
Article: Virtual screening and QSAR study of some pyrrolidine derivatives as α-mannosidase inhibitors for binding feature analysis.
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ABSTRACT: Virtual screening and QSAR analysis were carried out to investigate the binding features of (2R, 3R, 4S)-2-aminomethylpyrrolidine 3,4-diol and the functionalized pyrrolidine derivatives to the α-mannosidase I and II enzymes. The QSAR models (possessed considerable R(2), Q(2) values, etc.) suggested that the presence of polar property on the vdW surface (vsurf_W, vsurf_Wp, etc.) of the molecules is important along with the presence of aromatic rings (opr_violation) in the molecules (which also provide hydrophobicity to the molecules). The docking study performed on α-mannosidase I and II enzymes pointed that the main interactions occur by hydrogen bonds, hydrophobic π-π stacking contacts and salt bridges with the cation calcium (for α-mannosidase I) and close interaction with zinc ion (α-mannosidase II), respectively. The bond flexibility orientates the aromatic ring in the molecules toward the hydrophobic cavity for π-π stacking contacts with the aromatic amino acids (Phe528, Phe329 and Phe659 for α-mannosidase I and Trp95, Tyr269, Phe312, Tyr102 for α-mannosidase II). The pharmacophore analysis also supports the results derived from the docking and QSAR studies. Our results suggest that the best compound to inhibit both classes of α-mannosidase is the compound 30, which may be used to design similar and better inhibitors to next generation drugs.Bioorganic & medicinal chemistry 10/2012; · 2.82 Impact Factor -
Article: Human ether-a-go-go-Related Gene Channel Blockers and Its Structural Analysis for Drug Design.
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ABSTRACT: The human ether-a-go-go-related gene (hERG) is a K+ channel protein mainly expressed in the heart and the nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death. In this present review, we have focused the physicochemical properties responsible for the hERG blocking activity of structurally different compounds. The reported research works showed that the hydrophobicity on the van der Waals (vdW) surface of the molecules (aroused from the aromatic ring) necessary for the hERG blocking activity along with topological and electronic properties. The quinolizidine alkaloids (natural products) such as oxymatrine, sophoridine, sophocarpine and matrine carry the common molecular structure of O=C=N-C-C-C-N that possessed positive ionotropic effect and hERG blocking activity. Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial. The isoquinoline alkaloid, neferine (Nef) induces a concentration-dependent decrease in current amplitude (IC50 of 7.419 µM). Most of these natural product compounds contain non-flexible aromatic structures but have significant activity due to the presence of optimum hydrophobicity. Recent research works revealed that Eag and hERG channels are expressed by a variety of cancer cell lines and tissues. The Eag channel showed an oncogenic potential while hERG channels are associated with more aggressive tumors and have a role in mediating invasion. This review concluded that the consideration of physicochemical properties necessary for the hERG blocking activity will guide to develop novel drugs with less cardiotoxicity.Current drug targets 10/2012; · 3.93 Impact Factor -
Article: Molecular dynamics analysis of a series of 22 potential farnesyltransferase substrates containing a CaaX-motif.
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ABSTRACT: Protein farnesyltransferase (FTase) is an important target in many research fields, more markedly so in cancer investigation since several proteins known to be involved in human cancer development are thought to serve as substrates for FTase and to require farnesylation for proper biological activity. Several FTase inhibitors (FTIs) have advanced into clinical testing. Nevertheless, despite the progress in the field several functional and mechanistic doubts on the FTase catalytic activity have persisted. This work provides some crucial information on this important enzyme by describing the application of molecular dynamics simulations using specifically designed molecular mechanical parameters for a variety of 22 CaaX peptides known to work as natural substrates or inhibitors for this enzyme. The study involves a comparative analysis of several important molecular aspects, at the mechanistic level, of the behavior of substrates and inhibitors at the dynamic level, including the behavior of the enzyme and peptides, as well as their interaction, together with the effect of the solvent. Properties evaluated include the radial distribution function of the water molecules around the catalytically important zinc metal atom and cysteine sulfur of CaaX, the conformations of the substrate and inhibitor and the corresponding RMSF values, critical hydrogen bonds, and several catalytically relevant distances. These results are discussed in light of recent experimental and computational evidence that provides new insights into the activity of this enzyme.Journal of Molecular Modeling 09/2012; · 1.80 Impact Factor -
Article: Aryl- and Heteroaryl-Thiosemicarbazones Derivatives and Its Metal Complexes: A Pharmacological Template.
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ABSTRACT: In this review, we discuss the current patents regarding activity and properties (including coordination (chelation) properties) of aryl/heteroaryl thiosemicarbazone derivatives. The mode of action of the aryl/heteroaryl thiosemicarbazone derivatives is common and generally involves metal coordination with proteins or biological fluids that have metal ions into their structure. In addition, these molecules can also form multiple hydrogen bonds through their (thio) amide and N3 nitrogen that ensure a strong interaction with the receptor. In some cases, strong π-π interactions can also be observed. Special attention is given to pyridyl, bis-pyridyl, benzoylpyridyl and isatin thiosemicarbazone derivatives that exhibit significant anticancer, antiviral and other activities. This key biological role is often related with their capability to inhibit the enzyme ribonucleotide reductase, similar to what is observed with potent anticancer drugs such as Triapine and methisazone. Some isatin thiosemicarbazone derivatives have also P-glycoprotein (P-gp) modulating activity, which are currently being used in the design of novel inhibitors for the multidrug resistance cancer cells. Recent studies have also revealed that thiosemicarbazone can also inhibit topoisomerase II α enzyme. Additionally, recent patents on the thiosemicarbazones derivatives show that thiosemicarbazone can be combined with acceptable pharmaceutical excipient, used for the treatment of proliferative diseases as controlled or sustained release dosage form along with ionizing radiations (US20110152281, US20110245304, US20120172217).Recent patents on anti-cancer drug discovery. 09/2012; -
Article: The catalytic mechanism of mouse renin studied with QM/MM calculations.
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ABSTRACT: Hypertension is a chronic condition that affects nearly 25% of adults worldwide. As the Renin-Angiotensin-Aldosterone System is implicated in the control of blood pressure and body fluid homeostasis, its combined blockage is an attractive therapeutic strategy currently in use for the treatment of several cardiovascular conditions. We have performed QM/MM calculations to study the mouse renin catalytic mechanism in atomistic detail, using the N-terminal His6-Asn14 segment of angiotensinogen as substrate. The enzymatic reaction (hydrolysis of the peptidic bond between residues in the 10th and 11th positions) occurs through a general acid/base mechanism and, surprisingly, it is characterized by three mechanistic steps: it begins with the creation of a first very stable tetrahedral gem-diol intermediate, followed by protonation of the peptidic bond nitrogen, giving rise to a second intermediate. In a final step the peptidic bond is completely cleaved and both gem-diol hydroxyl protons are transferred to the catalytic dyad (Asp32 and Asp215). The final reaction products are two separate peptides with carboxylic acid and amine extremities. The activation energy for the formation of the gem-diol intermediate was calculated as 23.68 kcal mol(-1), whereas for the other steps the values were 15.51 kcal mol(-1) and 14.40 kcal mol(-1), respectively. The rate limiting states were the reactants and the first transition state. The associated barrier (23.68 kcal mol(-1)) is close to the experimental values for the angiotensinogen substrate (19.6 kcal mol(-1)). We have also tested the influence of the density functional on the activation and reaction energies. All eight density functionals tested (B3LYP, B3LYP-D3, X3LYP, M06, B1B95, BMK, mPWB1K and B2PLYP) gave very similar results.Physical Chemistry Chemical Physics 07/2012; 14(36):12605-13. · 3.57 Impact Factor -
Article: In silico based structural analysis of some piperidine analogs as farnesyltransferase inhibitors.
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ABSTRACT: In silico based QSAR and pharmacophore analyses of a series of piperidine derivatives were performed in order to investigate the structural features of the derivatives responsible for FTase inhibitory activity. The results derived from the QSAR analysis show that the FTase inhibitory activity mediated by the vdW surface area features such as partial charge (PEOE_VSA and Q_VSA) and v_surf (hydrophobic integy moment) of the molecules. The positive contribution of the partial charge descriptors such as Q_VSA_FPNEG and PEOE_VSA-4 reveal that the fractional negative charge on the vdW surface of the molecules and the aqueous solubility (LogS) of the molecules are important for the FTase inhibitory activity. While the hydrophobic integy moment reveals that a clear separation between the hydrophobic and the hydrophilic region in the molecules is important with electrostatic groups (fractional negative charge) for better activity. The pharmacophore analyses of the piperidine derivatives also show that the aromatic, acceptor and donor groups on the molecule favorable for the FTase inhibitory activity.Medicinal chemistry (Shāriqah (United Arab Emirates)) 06/2012; 8(5):853-64. · 1.64 Impact Factor -
Article: QSAR and Pharmacophore Analysis of a series of Piperidinyl Urea Derivatives as hERG Blockers and H3 Antagonists.
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ABSTRACT: In the present study, a computational based pharmacophore and structural analysis were performed on a series of piperidinyl urea derivatives, a limited number of compounds which have variation in structure and activities that exhibit hERG blocking and H3 antagonistic activities. The conducted QSAR studies demonstrated that the developed models are statistically significant, which have been confirmed through validation. The Q2 values for the models developed with hERG blocking activity are >0.8 and with the H3 antagonistic activity are >0.6. The descriptors contributed in the models show that the distributed polar properties on the vdW surface of the molecules are important for the hERG blocking activity. The vsurf_ descriptors (surface area, volume and shape) such as vsurf_DD13 and vsurf_Wp4 correlate with the H3 antagonistic activity of these compounds. The distances between the pharmacophore sites were measured in order to confirm their significance to the activities. The results reveal that the acceptor (acc), donor (don), hydrophobic (hyd) and aromatic/hydrophobic (aro/hyd) pharmacophore properties are favorable contours sites for both the activities. Also, our study reveals that the distance between the polar contours (acc, don, etc) has to be small for better hERG blocking activity. The distances between the aro/hyd to the polar groups should be higher for better hERG blocking activity. However, the H3 antagonistic activity for these series depends upon hydrophobic property of the molecules, particularly the hyd and the hyd/aro contours of the molecules. Hence, these results reveal the requirements on the structural properties and the distances between the pharmacophore contour sites of the molecules responsible for their hERG and H3 antagonistic activities.Current Drug Discovery Technologies 05/2012; -
Article: QSAR and pharmacophore analysis of thiosemicarbazone derivatives as ribonucleotide reductase inhibitors
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ABSTRACT: A series of α-N-heterocyclic carboxaldehyde thiosemicarbazones derivatives exhibit anticancer activity by inhibiting ribonucleotide reductase (RNR) enzyme was considered for the present computational study. The validated quantitative structure activity relationship (QSAR) models constructed with vsurf (HB7, WP7 and DW23) and molar refractivity (SMR_VSA5) descriptors yielded the cross-validated correlation coefficient of >0.6, shows that the models have sufficient predictive ability. The SMR_VSA5 descriptor is the main contributor for the activity prediction in all models, which measure the steric factors and bulkiness of the given molecules. The negative contribution of the molar refractivity descriptor shows that the molecular volume should be low with its polar properties. The vsurf descriptors are dependent on the structure connectivity and conformation (dimensions are measured in Å) which are useful in surface property prediction. The vsurf descriptors reveal that the surface polarity, hydrogen bond donor properties and hydrophilic contact surface of the molecules are important for the activity. The pharmacophore analysis results obtained from this study shows that the distance between the aromatic/hydrophobic and the PiN sites to the H-bond donor and acceptor groups should be connected with almost the same distance for significant RNR inhibitory activity. KeywordsRibonucleotide reductase–QSAR–Thiosemicarbazone–SMR_VSA5Medicinal Chemistry Research 04/2012; · 1.27 Impact Factor -
Article: Docking and molecular dynamics studies on the stereoselectivity in the enzymatic synthesis of carbohydrates
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ABSTRACT: Glycosidases constitute a vast family of enzymes that catalyze the breaking and formation of glycosidic bonds. The synthesized oligosaccharides, being crucial to life, are involved in many biochemical processes, particularly in the pharmaceutical and food industries. The proposed catalytic mechanism of retaining glycoside hydrolases (glycosidases) occurs via a double displacement mechanism involving a covalent glycosyl enzyme intermediate. During the transglycosylation reactions, the control of the stereoselectivity for the formation of the new bond remains a complicated problem in the chemical synthesis of oligosaccharides. In this paper, docking and molecular dynamics methods were used to study the second step of the mechanism of transglycosylation in retaining glycosidases from six microorganisms with known stereoselectivity. Using the natural substrates as donor and acceptor molecules, we were able to corroborate and provide structural information about the active site, the trapped monosaccharide acceptor and the bound intermediates during the step that precedes transglycosylation, as well as identify and understand the commonly displayed stereoselectivity by these glycosidases in nature. The information obtained with this procedure helps to recognize, explain and predict the stereoselectivity of the sugars studied. These kind of procedures can be used to improve the efficiency of large-scale industrial synthesis of a specific sugar.Theoretical Chemistry Accounts 04/2012; 122(5):283-296. · 2.16 Impact Factor -
Article: Analysis of the α-glucosidase inhibitory activity of chromenone derivatives based on their molecular features: a computational study.
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ABSTRACT: α-Glucosidase is one of the important enzymes in glucose digestion and its inhibitors are known to possess a large number of therapeutic effects. In this present investigation, we have performed structural feature analysis of some of these inhibitors namely, chromenone derivatives using the Molecular Operating Environment (MOE) software. The results of the QSAR study show that the derived models are statistically significant and were validated by external (test set) and internal (leave one out) methods. The crossvalidated correlation coefficients (Q2) of the models show that the training and test sets have the values > 0.6687. The physicochemical descriptors contributed for the models building in training set and complete data set show that the log of aqueous solubility (LogS) and the molar refractivity on the van der Waals surface area of the molecules (SMR_VSA4) positively contributed for the inhibitory activity. Further, the study also reveals that the polarizability and hydrogen bond acceptor/donor groups are important for the α-glucosidase inhibitory activity and these results are in agreement with the earlier studies obtained in our laboratory on α-glucosidase inhibitors which have shows that the polar surface area of the molecule is important for the interaction. The pharmacophore contours of the molecule also showed the importance of the polar surface property on the molecules. This computational analysis will help in the development of novel α-glucosidase inhibitors for various diseases.Medicinal chemistry (Shāriqah (United Arab Emirates)) 11/2011; 7(6):526-33. · 1.64 Impact Factor -
Article: Comparative structural analysis of α-glucosidase inhibitors on difference species: a computational study.
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ABSTRACT: Structural feature analysis of chlorogenic acid derivatives made up of varying lengths of alkyl groups as α-glucosidases inhibitors were performed by QSAR techniques. The statistically significant models derived from the study were validated by leave one out, Y-randomization and test set methods. The predictive capacity of the models was assessed by its validation parameters such as crossvalidated correlation coefficients (Q(2)), predictive residual analysis and other correlation parameters. The results obtained from the study show that the models were constructed with vsurf like properties (vsurf_ID4, vsurf_ID7 and vsurf_CW8), partial charge (Q_VSA_FNEG) and conformation dependent charged (dipoleX) descriptors. The integy moments of hydrophobicity descriptors (ID4 and ID7) are contributed for the inhibitory activity of the α-glucosidases enzymes of both the species. The vsurf_ID7 descriptor has contributed significantly (negatively) for the inhibitory activity prediction of α-glucosidases enzymes of S. cerevisiae. The partial negative charge on the surface of the molecules is detrimental for the activity, which reveals that the active site of the enzymes may have negatively charged groups. The pharmacophore analysis results also confirm the presence of hydrophilic properties on the vdW surface of the molecules. These results explain that the active sites of α-glucosidase enzymes of both the species have the same environment for the interaction. The alkyl side chain on the molecules is important for the pharmacokinetic behavior of the molecules and reduces the interaction energy of the molecules with the water. Hence, these results will be useful for designing novel molecules with multiple activities.Archiv der Pharmazie 10/2011; 345(4):265-74. · 1.71 Impact Factor -
Article: Structural analysis of structurally diverse α-glucosidase inhibitors for active site feature analysis.
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ABSTRACT: In the present investigation, a QSAR analysis on structurally diverse α-glucosidase inhibitors (andrographolide, chromenone, triazole derivatives) was performed and the developed models were validated by various validation methods (LMO, LOO, LSO, bootstrapping, Y-randomization and test set). The statistical parameters calculated for the models show that the developed models are statistically significant and have predicted the activities with small residual errors. The crossvalidated correlation coefficient (Q(2)) values obtained from different validation methods show >0.7 for both the models. Other correlations coefficient statistical parameters (R(2)(pred) and R(2)(m)) show that the developed models are reliable and robust. The leave-series-out (LSO) results reveal that the developed models can predict the activity of new compounds and its crossvalidated correlation coefficients' values are comparable with the Q(2) values obtained from other validation methods. The descriptors contributed in the selected models are suggested that the lower/reduced polarizability on the vdW surface area of the molecules and the presence of flexible bonds allow the substituents/side chains in the molecules with free movement and with lesser stretching energy which are favourable for the α-glucosidase inhibitory activity. These results reveal that the developed models are statistically significant and can be used with other molecular modelling works for designing novel α-glucosidase inhibitors with multiple activities (HIV, diabetics, cancer, etc).Journal of Enzyme Inhibition and Medicinal Chemistry 09/2011; 27(5):649-57. · 1.62 Impact Factor -
Article: In silico-based structural analysis of arylthiophene derivatives for FTase inhibitory activity, hERG, and other toxic effects.
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ABSTRACT: In the present investigation, the authors have performed an in silico-based analysis on a series of arylthiophene derivatives for the determination of their structural features responsible for farnesyltransferase (FTase) inhibitory activity, hERG blocking activity, and toxicity by quantitative structure-activity relationship and pharmacophore analysis techniques. The statistically significant models derived through multiple linear regression analysis were validated by different validation methods. The applicability of the descriptors contributed in the selected models show that the polar and polarizable properties on the van der Waals (vdW) surface area of the molecules are important for the FTase inhibitory and hERG blocking activities, while being detrimental for the toxicity of the molecules. It is interesting to note that the topological properties, molecular flexibility, and connectivity of the molecules are positively correlated to all the activities (FTase inhibition, hERG blocking, and toxicity). This implies that the flexibility of the molecules is the common feature for interaction in all targets, whereas the presence of polar groups on the molecular surface (vdW) is a determinant for the favorable (FTase inhibition) or unwanted effect (hERG blocking and toxicity) of the molecules. The pharmacophore analysis of the molecules demonstrated that the aromatic/hydrophobicity and polarizability features are important pharmacophore contours favorable for these activities.Journal of Biomolecular Screening 08/2011; 16(9):1037-46. · 2.05 Impact Factor -
Article: The Catalytic Mechanism of RNA Polymerase II
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ABSTRACT: Eukaryotic RNA polymerase II (RNAP II) transcribes the DNA into mRNA. The presence of two metal ions (usually Mg2+) and conserved aspartate residues in the active sites of all nucleic acid polymerases led to the adoption of a universal catalytic mechanism, known as the “two metal ion catalysis”. In this scheme, it is assumed that the coordination shell of Mg2+ (geometry, number, and identity of the ligands) is basically the same for all of the enzymes, despite the significant differences in sequence and structure commonly found in multisubunit RNA polymerases versus single-subunit RNA polymerases and DNA polymerases. Here, we have studied the catalytic mechanism of RNAP II and found very interesting variations to the postulated mechanism. We have used an array of techniques that included thermodynamic integration free energy calculations and electronic structure calculations with pure DFT as well as hybrid DFT/semiempirical methods to understand this important mechanism. We have studied four different catalytic pathways in total, resulting from different combinations of proton donors/acceptors for the two proton transfers experimentally detected (deprotonation of the 3′ hydroxyl of the terminal nucleotide (HORNA) and protonation of pyrophosphate). The obtained data unambiguously show that the catalytic mechanism involves the deprotonation of HORNA by a hydroxide ion coming from the bulk solvent, the protonation of pyrophosphate by the active site His1085, and the nucleophilic attack to the substrate by O−RNA. The overall barrier is 9.9 kcal/mol. This mechanism differs from those proposed in the identity of the general acid. The deprotonation of the HORNA and the transition state for the nucleophilic attack are similar to some (but not all) of the family members.03/2011; -
Article: Structural feature study of benzofuran derivatives as farnesyltransferase inhibitors.
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ABSTRACT: Ras proteins are small GTPases (G-proteins) that play a key role in cell growth and cell proliferation in the mitogen-activated protein kinase signal transduction pathway. Farnesylation is a critical step for membrane binding and the biological function of G-proteins. In the present investigation, we have studied the structural features of some molecules that are acting on the farnesyltransferase (FTase) enzyme for the inhibition of the farnesylation step in G-proteins. The benzofuran derivatives have activity against FTase inhibition and antiproliferative activity on QG56 cell lines. The result obtained from the quantitative structure-activity relationship study of these compounds shows that the models have significant predictive power and stability, as shown by statistical parameters such as R(2), Q(2), R(2)(pred), R(2)(m), F-value, Durbin-Watson, variable inflation factor values, Mahalanobis, and Cook's distances. The contribution of each descriptor for the activities (β-coefficients) reveals that the P-VSA descriptors (van der Waals surface area descriptors) such as vsa_pol, vsa_acc and SMR_VSA3 are the major contributors for the activity, along with other descriptors such as the partition coefficient, the partial charge, the atom and bond count and the adjacency, and distance descriptors. Earlier study on the FTase enzyme in our laboratory reveals that the existence of positively-charged groups on the FTase active site is important for drug design. It is also showing that the presence of hydrogen bonding donor and acceptor groups, together with negatively charged substituents is critical for improved activity by this series of molecules. These results offer important clues for the development of novel FTase inhibitors.Journal of Enzyme Inhibition and Medicinal Chemistry 03/2011; 26(6):777-91. · 1.62 Impact Factor -
Article: Prediction of the relationship between the structural features of andrographolide derivatives and α-glucosidase inhibitory activity: a quantitative structure-activity relationship (QSAR) study.
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ABSTRACT: In order to predict the structural features responsible for α-glucosidase inhibitory activity, a quantitative structure-activity relationship (QSAR) analysis was performed on a series of andrographolide derivatives. To determine the quantitative relationship for the statistically significant models in terms of r (>0.8), F (99%) and Q(2) (>0.71) values were selected. The promising results we obtained could be used to predict the structural requirements for the inhibition of α-glucosidase activity. The models developed included: subdivided surface area, adjacency, surface volume and shape, molecular orbital package (MOPAC) and partial charge descriptors and showed a high correlation with the inhibitory activity. The descriptors used revealed that a van der Waals (vdW) surface with significant polar volume is favourable to the activity. The positive effect of the shape descriptors; PM3-LUMO and vsurf_wp7 and the negative effect of GCUT_PEOE_2 indicated that the active site may contain some nucleophilic positions that could interact with the ligand and the hydrogen acceptor and/or donor groups for hydrogen bonding with inhibitors.Journal of Enzyme Inhibition and Medicinal Chemistry 02/2011; 26(1):78-87. · 1.62 Impact Factor -
Article: Chemical behavior of methylpyranomalvidin-3-O-glucoside in aqueous solution studied by NMR and UV-visible spectroscopy.
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ABSTRACT: In the present work, the proton-transfer reactions of the methylpyranomalvidin-3-O-glucoside pigment in water with different pH values was studied by NMR and UV-visible spectroscopies. The results showed four equilibrium forms: the methylpyranomalvidin-3-O-glucoside cation, the neutral quinoidal base, the respective anionic quinoidal base, and a dianionic base unprotonated at the methyl group. According to the NMR data, it seems that for methylpyranomalvidin-3-O-glucoside besides the acid-base equilibrium between the pyranoflavylium cation and the neutral quinoidal base, a new species is formed at pD 4.88-6.10. This is corroborated by the appearance of a new set of signals in the NMR spectrum that may be assigned to the formation of hemiketal/cis-chalcone species to a small extent. The two ionization constants (pK(a1) and pK(a2)) obtained by both methods (NMR and UV-visible) for methylpyranomalvidin-3-O-glucoside are in agreement (pK(a1) = 5.17 ± 0.03; pK(a2) = 8.85 ± 0.08; and pK(a1) = 4.57 ± 0.07; pK(a2) = 8.23 ± 0.04 obtained by NMR and UV-visible spectroscopies, respectively). Moreover, the fully dianionic unprotonated form (at the methyl group) of the methylpyranomalvidin-3-O-glucoside is converted slowly into a new structure that displays a yellow color at basic pH. On the basis of the results obtained through LC-MS and NMR, the proposed structure was found to correspond to the flavonol syringetin-3-glucoside.The Journal of Physical Chemistry B 02/2011; 115(6):1538-45. · 3.70 Impact Factor -
Article: Topological, hydrophobicity, and other descriptors on α-glucosidase inhibition: a QSAR study on xanthone derivatives.
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ABSTRACT: Quantitative structure activity relationship analysis was performed on a series of xanthone derivatives to establish the structural features required for α-glucosidase inhibitory activity. The computational and statistical analysis was performed with V life MDS (Molecular Design Suite) and Statistica software. The selected models show significant predictive power, stability, and reliability in terms of cross-validated correlation coefficient (Q(2)(cv) > 0.74 and Q(2)(test) > 0.5) and other validation parameters. The results show that the SaaaC count, MMFF_6 and dipole moment are mainly contributed for the activity along with the hydrophobicity descriptors. It describes that heteroatoms (oxygen atom connected with carbon atom) in the molecules are favourable for α-glucosidase inhibitory activity. The E-state count descriptor suggests that when carbon atoms connected with three aromatic bonds and hydrogen or other atoms are favourable for the activity. The SAHA and SAMH descriptors show that the hydrophilic area in the molecule is important for the activity while high hydrophilicity is unfavourable for the activity. This study concluded that hydrophilic, polar and/or electron negative groups, which are responsible for hydrogen bonding and interaction with the enzyme for favourable activity.Journal of Enzyme Inhibition and Medicinal Chemistry 02/2011; 26(6):755-66. · 1.62 Impact Factor
Top co-authors
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Institutions
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2005–2013
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University of Porto
- • Departamento de Química e Bioquímica
- • Departamento de Química
Porto, Distrito do Porto, Portugal
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2009–2010
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REQUIMTE
Caparica, Distrito de Setubal, Portugal
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