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Abstract: Despite the tremendous progress that has occurred in recent years in cell biology and oncology, in chemical, physical and computer sciences, the disease cancer has continued as the major cause of death globally. Research organizations, academic institutions and pharmaceutical companies invest huge amounts of money in the discovery and development of new anticancer drugs. Though much effort is continuing and whatever available approaches are being attempted, the success of bringing one effective drug into the market has been uncertain. To overcome problems associated with drug discovery, several approaches are being attempted. One such approach has been the use of known, approved and marketed drugs to screen these for new indications, which have gained considerable interest. This approach is known in different terms as “drug repositioning or drug repurposing.” Drug repositioning refers to the structure modification of the active molecule by synthesis, in vitro/ in vivo screening and in silico computational applications where macromolecular structure-based drug design (SBDD) is employed. In this perspective, we aimed to focus on the application of repositioning or repurposing of essential drug moieties present in drugs that are already used for the treatment of some diseases such as diabetes, human immunodeficiency virus (HIV) infection and inflammation as anticancer agents. This review thus covers the available literature where molecular modeling of drugs/enzyme inhibitors through SBDD is reported for antidiabetics, anti-HIV and inflammatory diseases, which are structurally modified and screened for anticancer activity using respective cell lines.

Alzheimer's Disease is a complex progressive neurodegenerative disorder characterized by neurofibrillary tangles and senile plaques in various parts of the brain particularly cerebral cortex affecting memory and cognition. Nuclear receptors such as Peroxisome proliferator-activated receptor γ [PPAR-γ] is reported to have a role in lipid and glucose homeostasis in the brain, reduces the synthesis of Aβ (beta-amyloid plaques) and also regulates mitochondrial biogenesis and inhibit the neuro-inflammation, which contributes for the improvement in the cognitive function in AD. Hence PPAR-γ is one of the newer targets for the researchers to understand the pathology of AD and to evolve the novel strategy to retard/reverse the progression of AD. PPAR-γ agonists such as Rosiglitazone and Pioglitazone have shown promising results in AD by decreasing neuro-inflammation and restoring glucose dysmetabolism leading to a reduction in neuronal deterioration. These agonists possess poor blood-brain permeability and are poor candidates for clinical use in AD. Therefore, search, design, and development for new PPAR- γ agonists with improved BBB penetration ability are imperative. The present work deals with the use of computational tools and techniques such as molecular docking, molecular dynamics to discover PPAR-γ agonists from the unexplored Seaweed Metabolite Database and predicts it's toxicological and physiochemical profile, thereby saving time and resources. Out of 1,110 seaweed compounds, the hit molecule BS052 displayed a strong binding affinity towards PPAR-γ, which possessed better lipid solubility indicating the potential to be considered as a PPAR-γ agonist, which may be useful in the management of AD.Communicated by Ramaswamy H. Sarma.

Fibroblast growth factor receptor (FGFR) plays a vital role in tissue regeneration, angiogenesis, and embryogenesis. 3D-QSAR and molecular modeling methods are widely used for designing novel compounds for the determination of inhibitory activity against the biological target. In the present study, 3D-QSAR (CoMFA and CoMSIA) analysis was performed on 1, 6-naphthyridines, and pyridopyrimidines as potential FGFR inhibitors as anticancer agents. The best CoMFA and CoMSIA models were generated from test and training set derivatives with leave-one-out correlation coefficients (

The conserved three-dimensional structure of receptor tyrosine kinases (RTKs) has been varyingly observed in prokaryotes to humans that actively participate in the phosphorylation process of tyrosine residues in the protein, which results in the alteration of protein's function. Mutation and transcriptional or post-translational modifications lead to a deregulation of kinases, which ultimately fallout into the development of pathological conditions like cancer. The human genome encodes two kinds of tyrosine kinases: non-receptor tyrosine kinases (NRTKs) and receptor tyrosine kinases (RTKs). Among these kinases, VEGF/VEGFR-2 signaling cascade is an important target to develop novel small-molecule inhibitors for the therapy of abnormal angiogenesis incorporated with cancer. Due to advances in the knowledge of the catalytic domain and 'DFG-motif' region, selective 'DFG-in' (type I) and 'DFG-out' (type II) VEGFR-2/KDR inhibitors were successfully developed, and some are in different phases of a clinical trial. 'DFG-out' (inactive) confirmation has significant advantages over 'DFG-in' (active) confirmation concerning the affinity of the ATP at the catalytic domain. Further, in the catalytic domain, between front and back cleft, smaller gatekeeper residue (Val916) present; therefore, selectivity against VEGFR-2 could be precisely achieved. In this review, small molecule type II/'DFG-out' inhibitors, their conformation, interaction at receptor binding pocket, and structural requirements to inhibit VEGFR-2 at the molecular level are discussed.HighlightsVEGFR-2 is a type of membrane-bound receptor tyrosine kinases (RTKs) that regulates the process of vasculogenesis and angiogenesis.Small molecule first-generation type I, 'DFG-in' and second-generation type II, 'DFG-out' VEGFR-2 inhibitors exhibit clinical benefits in the treatment of aberrant angiogenesis associated with cancer.Molecular docking of FDA approved and novel type II inhibitors were performed using X-ray crystal structures of VEGFR-2; binding site analysis was carried out.Structural requirements for the inhibition of VEGFR-2 were identified.

Cancer stem cells (CSCs) are involved in recurrent hepatocellular carcinoma (HCC), yet there is a lack of effective treatment that targets these CSCs. CD44+ and CD133+ CSCs are markedly expressed in HepG2 cells and were isolated and characterized using fluorescence-activated cell sorting (FACS) analysis. Since piperine is known as an effective molecule against metastasis, we thought to investigate the effect of piperine against CD44+/CD133+ CSCs. Herein, piperine was found to be active against these CSCs. Also, it was found appropriate to respite at the 'subG0/G1 and G0/G1′ phase of the cell cycle analysis, respectively. TGF-β activated epithelial-mesenchymal transition (EMT) has been involved in the invasion and metastasis of HepG2 cells in hepatocellular carcinoma. Therefore, we next investigated the effect of piperine on different biomarkers that remarkably takes part in the process of EMT using flow cytometric analysis. Piperine was found able to repress the epithelial marker (E-cadherin) but was unable to restore the level of Vimentin (mesenchymal marker) and SNAIL (EMT-inducing transcription factor). Therefore, the findings of this study revealed that piperine could be an effective treatment strategy for recurrent hepatocarcinogenesis.

Phosphodiesterase-4 (PDE 4) enzyme has emerged as an invaluable target for the treatment of asthma, chronic obstructive pulmonary disease and rheumatoid arthritis. These findings have generated widespread interest in PDE-4 inhibitors as a potential molecular target for the development of new anti-inflammatory drugs. A series of N-substituted cis-tetra- and cis-hexahydrophthalazinone derivatives have been reported as novel, selective PDE-4 inhibitors with potent anti-inflammatory activity. In order to gain further insights into the structural requirements of novel series of N-substituted cis-tetra and cis-hexahydrophthalazinone derivatives as PDE-4 inhibitors, a three-dimensional quantitative structure activity relationship (3D-QSAR) was performed using Genetic Function Approximation (GFA). The QSAR model was generated using a training set of 45 molecules and the predictive ability of the resulting each model was assessed using a test set of 9 molecules. The internal and external consistency of final QSAR model was 0.675 and 0.750 respectively. Analysis of results from the present QSAR study indicates that shape and structural descriptors strongly govern the PDE-4 enzyme inhibitory activity. This QSAR study highlights the structural features required for PDE-4 enzyme inhibition and may be useful for design of potent PDE-4 inhibitors.

Aim: To study the effect of a new biphenyl synthetic compound showing interactions with the active site of protein tyrosine phosphatase 1B by docking and molecular dynamics, VMNS2e in streptozotocin-induced diabetic nephropathy in rats with various renal function parameters and renal ultrastructure. Methods: Streptozotocin (55 mg/kg)-induced diabetic rats were orally treated once daily with VMNS2e (30, 60, and 120 mg/kg) for 8 weeks. The body weight and blood glucose levels of the rats were recorded during the study period. After 8 weeks of treatment creatinine clearance, urinary protein, blood urea nitrogen, urinary albumin excretion rate, and insulin levels were measured. An ultrastructure study of the kidney tissue was performed and the glomerular basement membrane thickness was measured. Results: Eight weeks of VMNS2e treatment significantly reduced the fasting blood glucose level, attenuated elevating blood urea nitrogen levels, and reduced glomerular basement membrane thickness. Conclusion: It is concluded that VMNS2e treatment at 30 and 60 mg/kg, when given for 8 weeks, partly ameliorated early diabetic nephropathy in diabetic rats.

Cyclooxygenase-2 (COX-2) inhibitors are widely used for the treatment of pain and inflammatory disorders such as rheumatoid arthritis and osteoarthritis. A series of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives has been reported as COX-2 inhibitors. In order to understand the structural requirement of these COX-2 inhibitors, a ligand-based pharmacophore and atom-based 3D-QSAR model have been developed. A five-point pharmacophore with four hydrogen bond acceptors (A) and one hydrogen bond donor (D) was obtained. The pharmacophore hypothesis yielded a 3D-QSAR model with good partial least-square (PLS) statistics results. The training set correlation is characterized by PLS factors (r (2) = 0.642, SD = 0.65, F = 82.7, P = 7.617 e - 12). The test set correlation is characterized by PLS factors (Q (2) (ext) = 0.841, RMSE = 0.24,Pearson-R = 0.91). A docking study revealed the binding orientations of these inhibitors at active site amino acid residues (Arg513, Val523, Phe518, Ser530, Tyr355, His90) of COX-2 enzyme. The results of ligand-based pharmacophore hypothesis and atom-based 3D-QSAR give detailed structural insights as well as highlights important binding features of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as COX-2 inhibitors which can provide guidance for the rational design of novel potent COX-2 inhibitors.

The conformational structure of propranolol, a β-adrenergic blocking drug, has been investigated by pcilo calculations and 270-MHz proton nuclear magnetic resonance in D 2 O solution. The molecules coexist in at least two conformational states in solution with a low energy barrier. Both preferred conformations have extended structures which allow a three-point drug-receptor binding involving the aromatic moiety, the β-hydroxyl group, and -NH + 2 groups of propranolol. The previously postulated "rigid" bicyclic structure does not exist to an appreciable extent in D 2 O solution.

From the earlier quantitative structure–activity relationship (QSAR) and molecular modeling studies, a series of quinoline derivatives 5a–h mimicking terbinafine and containing different bulky aromatic rings in the side chain were designed using LeapFrog, a de novo drug design program. The designed compounds were synthesized and screened for antifungal activity in vitro against C. albicans. Of the ten compounds designed and synthesized, compounds 5c, d, f, h, and i exhibited minimum inhibitory concentration (MIC) in the range 4–25 μg/ml and were further evaluated for oral toxicity in animal model. The pharmacokinetic properties for these compounds were estimated in silico and compared with terbinafine. Compound 5h, N-methyl-N-[(2-naphthyl)methyl]-8-quinolinemethanamine, was found to be least toxic, possessing pharmacokinetic parameters close to those of terbinafine.

Benzofurans are a class of antifungal agents reported to act by selective inhibition of the N-myristoyltransferase (Nmt) enzyme in fungal cells. A three-dimensional quantitative structure–activity relationship (3D-QSAR) was performed on a series of 29 molecules to find correlation between various physicochemical descriptors and Nmt inhibition. QSAR equations were evaluated using a training set 24 molecules and an external test set of 5 molecules. The statistical quality of the QSAR models was evaluated using the parameters r2, rcv2, and the rpred2 measure. The results obtained indicated that the enzyme inhibitory activity of benzofuran analogues strongly depends on structural factors as expressed by hydrogen-bond acceptors and spatial factors as expressed by the principle moment of inertia in the X (PMI_X) and Y directions (PMI_Y).

Novel copper(II) complexes of curcumin Knoevenagel condensates and their Schiff bases have been synthesized and characterized. All copper complexes possess distorted square‐planar geometries with 1:1 metal to ligand stoichiometry capable of stabilizing Cu2+/Cu1+ redox couples in the range 0.34 to 0.40 V. ESR spectral features are consistent with g‖>g⊥>2.0 suggesting monomeric nature of copper complexes having dx 2 −y 2 ground state.

Novel curcumin analogs were synthesized using Knoevenagel condensation to convert enolic diketones of curcumin into non-enolizable ones and Schiff bases were prepared using a bioactive thiosemicarbazide pharmacophore. Copper(II) conjugates of all synthesized ligands were prepared and structurally characterized as well as evaluated for their potential of inhibiting TNF-induced NF-kappaB activation and proliferation in human leukemic KBM-5 cells wherein compound 13 was found to be more potent than curcumin. Compounds were further examined on other tumor cell lines such as Jurkat, H1299, and MM1, respectively.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed on a series of Schiff bases of hydroxysemicarbazide analogues using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods with their antitumor activities against L1210 cells. The models were generated using 24 molecules, out of which one molecule was a commercially available ribonucleotide reductase (RR) inhibitor, hydroxyurea (HU), and the predictive ability of the resulting each model was evaluated against a test set of four molecules. Maximum common substructure (MCS)-based method was used for alignment and compared with the known alignment methods. The QSAR models from both methods exhibited considerable correlative and predictive properties. Inclusion of additional descriptor ClogP improved the statistics of CoMFA model significantly. Both methods strongly suggest the necessity of lipophilicity for antitumor activity. CoMFA and CoMSIA methods predicted HU optimally, indicating a similar mechanism of action for the molecules considered for generating the models and HU to inhibit the tumor cells. The analysis of CoMFA contour maps provided insight into the possible modification of the molecules for better activity.

A homology model of Mycobacterium avium complex dihydrofolate reductase (MAC DHFR) was constructed on the basis of the X-ray crystal structure of Mycobacterium tuberculosis (Mtb) DHFR. The homology searching of the MAC DHFR resulted in the identification of the Mtb DHFR structure (PDB 1DF7) as the template for the model building. The MAC enzyme sequence was aligned to that of the Mtb counterpart using a modified Needleman and Wunsch methodology. The initial geometry to be modeled was copied from the template, either fully or partially depending on whether the residues were conserved or not, respectively. Using a randomized modeling procedure, 10 independent models of the target protein were built. The cartesian average of all the model structures was then refined using molecular mechanics. The resulting model was assessed for stereochemical quality using a Ramachandran plot and by analyzing the consistency of the model with the experimental data. The structurally and functionally important residues were identified from the model. Further, 5-deazapteridines recently reported as inhibitors of MAC DHFR were docked into the active site of the developed model. All the seven inhibitors used in the docking study have a similar docking mode at the active site. The network of hydrogen bonds around the 2,4-diamino-5-deazapteridine ring was found to be crucial for the binding of the inhibitors with the active site residues. The 5-methyl group of the inhibitors was located in a narrow hydrophobic pocket at the bottom of the active site. The relative values of the three torsion angles of the inhibitors were found to be important for the proper orientation of the inhibitor functional groups into the active site.

4-(Bromomethyl) coumarins 1 have been reacted with vanillins, 2 and 2A to obtain the corresponding ethers 3 and 5. Ethers 3 have been reacted with ethyl cyanoacetate to obtain the unsaturated esters 4. Ethers 5 have been converted to the corresponding 4-(2'-benzo[b] furanyl) coumarins 6 by an intramolecular aldol condensation. Eight compounds have been screened for their anti-inflammatory activity. Out of these the 5,6-benzo-4-2'-benzo[b]furanyl) coumarin (6c) and the aryloxymethyl coumarin (4) with p-formyl group were found to be most active.

D-QSAR and molecular modeling was performed on a series of benzofuran/benzothiophene biphenyls as protein tyrosine phosphatase 1B (PTP 1B) inhibitors with anti-hyperglycemic activity. Evaluation of 92 compounds served to establish the model, which was validated by evaluation of an external set of 26 compounds. The lowest energy conformer of most active compound (compound 54) obtained from simulated annealing was used as a template structure for the alignment. The best predic- tions were obtained with the CoMFA model from RMS fit and A log P as additional descriptor (r 2 =0.615, r 2 =0.842), and with the CoMSIA combined steric, electrostatic, and lipophilic fields (r 2 =0.597, r 2 =0.910). The 3D-QSAR model was then superimposed to the PTP 1B active site, giving direct contour maps of the different fields. Further comparison of the contour maps from the 3D-QSAR showed high level of compatibility with the active site of PTP 1B enzyme. # 2002 Elsevier Science Ltd. All rights reserved.

Quantitative structure–activity relationship (QSAR) paradigm, using genetic function approximation (GFA) technique was used to examine the correlations between the calculated physicochemical descriptors and the in vitro activities (3′-processing and 3′-strand transfer inhibition) of a series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors. Depending on the chemical structure, all molecules were divided into two classes—catechols and noncatechols. Eighty-one molecules were used in the present study and they were divided into training set and test set. The training set in each class consisted of 35 molecules and QSAR models were generated separately for both catechols and noncatechols. Equations were evaluated using internal as well as external test set predictions. Models generated for catechols show that electronic, shape related, and thermodynamic parameters are important whereas for noncatechols, spatial, structural, and thermodynamic properties play an important role for the activity.

Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies for 3-aryloxazolidin-2-one antibacterials were performed using the genetic function approximation algorithm. This study was performed using 60 compounds, in which the QSAR models were developed using a training set of 50 compounds. The in vitro minimum inhibitory concentration (MIC) against Staphylococcus aureus SFCO-1a was used for the study. The predictive ability of the QSAR model was evaluated by using a test set of 10 compounds. The statistical quality of the QSAR models was assessed using statistical parameters r 2 , r 2 cv (cross-validated r 2 ), r 2 pred (predictive r 2 ) and lack of fit measure (LOF). The results obtained indicate that the antibacterial activity of the 3-aryloxazolidin-2-ones is strongly dependent on electronic factor as expressed by lowest unoccupied molecular orbital energy (LUMO), spatial factor as expressed by density and thermodynamic factors accounted for by molar refractivity and heat of formation. The model is presently being used to design and predict new potent molecules prior to synthesis.

A three-dimensional pharmacophore model has been generated for Candida albicans MyristoylCoA: protein N-myristoyltransferase (NMT) inhibitors, using the software program CATALYST. The in vitro NMT inhibitory activity of a series of peptidic inhibitors was used for pharmacophore generation. The effect of altering the control parameters and feature selection was studied to arrive at the pharmacophore model. The selection of the best hypothesis model was based on the total cost, predictive ability, difference in the cost from the null hypothesis and alignment of the training set compounds on to the hypothesis. The pharmacophore model selected has four features; one hydrophobic, two hydrogen bond acceptor and one positive ionisable function. Groups identified as necessary by scanning alanine mutagenesis studies of the peptidic substrate of C. albicans NMT, have been identified as pharmacophore features. Comparison of the ligand binding with the enzyme in the crystal structure of NMT and that proposed by the phamacophore is consistent. The pharmacophore thus generated can be used as a template for designing non-peptidic inhibitors of NMT.

Terbinafine and its analogues, which are a major class of non-azole antifungal agents, are known to act by inhibition of squalene epoxidase enzyme in fungal cells. We have performed a quantitative structure-activity relationship (QSAR) study on a series of 92 molecules using different types of physicochemical descriptors. Inhibitors were divided into five classes depending upon chemical structure. QSAR models were generated for correlation between antifungal activity against Candida albicans using genetic function approximation (GFA) technique. Equations were evaluated using internal as well as external test set predictions. Models generated for all these classes show that steric properties and conformational rigidity of side chains play an important role for the activity. The present QSAR analysis agrees with the results of the previously reported CoMFA study.

A three-dimensional quantitative structure-activity relationship (QSAR) study using the comparative molecular field analysis (CoMFA) method was performed on a series of interleukin 1-beta converting enzyme (ICE) inhibitors. The compounds studied have been reported to be time-dependent inhibitors of ICE. This study was performed using 49 compounds, in which the CoMFA models were developed using a training set of 39 compounds. All the compounds were modeled using the X-ray crystal structure of tetrapeptide aldehyde inhibitor/ICE complex. The inhibitor compounds were considered both as neutral species and as P1 carboxylate ionized species. Superimpositions were performed using two alignment rules, namely, an alignment of the structures based on RMS fitting of the backbone heavy atoms of each structure to compound 2 and an alignment based on SYBYL QSAR rigid body field fit of the steric and electrostatic fields of the molecules to the fields of compound 2. Use of LUMO energies or ClogP as additional descriptors in the QSAR table did not improve the significance of the CoMFA models. Steric and electrostatic fields of the inhibitors were found to be the relevant descriptors for structure-activity relationships. The predictive ability of the CoMFA model was evaluated by using a test set of 10 compounds (r2pred as high as 0.859). Further comparison of the coefficient contour maps with the steric and electrostatic properties of the receptor show a high level of compatibility.

Protein tyrosine phosphatase 1B (PTP 1B), a negative regulator of insulin receptor signaling system, has emerged as a highly validated, attractive target for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and obesity. As a result there is a growing interest in the development of potent and specific inhibitors for this enzyme. This quantitative structure-activity relationship (QSAR) study for a series of formylchromone derivatives as PTP lB inhibitors was performed using genetic function approximation (GFA) technique. The QSAR models were developed using a training set of 29 compounds and the predictive ability of the QSAR model was evaluated against a test set of 7 compounds. The internal and external consistency of the final QSAR model was 0.766 and 0.785. The statistical quality of QSAR models was assessed by statistical parameters r2, r2 (crossvalidated r2), r2pred (predictive r2) and lack of fit (LOF) measure. The results indicate that PTP lB inhibitory activity of the formylchromone derivatives is strongly dependent on electronic, thermodynamic and shape related parameters.

Different modes of binding of transition state mimics: amide, phosphonate and difluoro ketone, to human synovial fluid phospholipase A2 (HSF PLA2) are studies by molecular dynamics simulations computed in solvent. The results are analysed in the light of primary binding sites. Hydrogen bonding interaction plays an important role for amino acids such as Gly32, Val30, and Glu55, apart from the well known active site residues viz Asp48, Gly25, Gly29, Gly31, His27, His47, Lys62, Phe23, Asn114 and Tyr112. In addition, the hydrogen bonding interaction between Sn-1 tetrahedral phosphonate group of amide and difluoro ketone inhibitors and crystallographic water molecules (H2O 523, H2O 524 and H2O 401) seems to have a significant role. Many of the active site charged residues display considerable movement upon ligand binding. The structural effects of ligand binding were analyzed from RMS deviations of C alpha in the resulting energy-minimized average structures of the receptor-ligand complexes. The values of the RMS deviations differ among the HSF PLA2s, in a pattern that is not the same for the three complexes. This suggests that ligands with different pharmacological efficacies induce different types of conformational changes of the receptor. Our active-orientation model is, at least qualitatively, consistent with experimental data and should be useful for the rational design of more potent inhibitors.

To study the effect of a new biphenyl synthetic compound showing interactions with the active site of protein tyrosine phosphatase 1B by docking and molecular dynamics, VMNS2e in streptozotocin-induced diabetic nephropathy in rats with various renal function parameters and renal ultrastructure.Streptozotocin (55 mg/kg)-induced diabetic rats were orally treated once daily with VMNS2e (30, 60, and 120 mg/kg) for 8 weeks. The body weight and blood glucose levels of the rats were recorded during the study period. After 8 weeks of treatment creatinine clearance, urinary protein, blood urea nitrogen, urinary albumin excretion rate, and insulin levels were measured. An ultrastructure study of the kidney tissue was performed and the glomerular basement membrane thickness was measured.Eight weeks of VMNS2e treatment significantly reduced the fasting blood glucose level, attenuated elevating blood urea nitrogen levels, and reduced glomerular basement membrane thickness.It is concluded that VMNS2e treatment at 30 and 60 mg/kg, when given for 8 weeks, partly ameliorated early diabetic nephropathy in diabetic rats.

Molecular modeling studies were performed on a diverse set of 24 cytochrome P-45014αDM inhibiting azole antifungals that demonstrate different degrees of biological activity. The studied compounds, which have been reported to be active in vitro against Candida albicans, were divided into a training set of 20 compounds and a test set of 4 compounds. In an effort to develop a ligand-binding model for the cytochrome P-45014αDM receptor, a pharmacophore mapping program (Apex-3D) was used to search structural features that are common to ligands that exhibit moderate to high antifungal activity. Apex-3D then was utilized to propose a common biophoric region that included one low-energy conformation of each compound in the training set. These aligned structures suggested a three-point pharmacophore map (two atom-centered descriptors and one aromatic ring centroid) for the azole antifungals. The resulting alignment was used in a comparative molecular field analysis (CoMFA) study in an attempt to correlate the ste...

A series of computations were performed to derive a strategy for the prediction of binding affinities of non-peptidic human immunodeficiency virus-1 (HIV-1) protease inhibitors. This paper describes the development of a 3D quantitative structure−activity relationship (3D-QSAR) methodology by using receptor information of HIV-1 protease. The docking and molecular dynamics simulations were performed on a model ligand/enzyme complex to optimize the variables involved in the generation of ligand/enzyme models. The protonation scheme of the active site aspartic acid residues of HIV-1 protease was derived from a computational study. The active site aspartate is monoprotonated with a proton placed on the OD1 atom of the ASP B25. This protocol of docking and molecular dynamics (MD) simulation was then used to derive the ligand−enzyme complexes of the molecules used in the present study. The molecular mechanics interaction descriptors were calculated from these ligand/enzyme models. A partial least squares (PLS) m...

A three-dimensional quantitative structure activity relationship using the eigen value analysis (EVA) paradigm applied to 41 HIV-1 integrase inhibitors that inhibit integrase mediated cleavage (3‘-processing step) and integration (3‘-strand transfer step) in vitro was performed. The training set consisted of 35 molecules from five structurally diverse classes: salicylhydrazines, lichen acids, coumarins, quinones, and thiazolothiazepines. Models derived using semiempirical (MOPAC AM1 and PM3) calculated normal-mode frequencies were compared. The predictive ability of each resultant model was evaluated using a test set comprised of six molecules belonging to a different structural class: hydrazides. Models derived using AM1 method showed considerable internal as well as external predictivity (r2cv = 0.806, r2pred = 0.761 for 3‘-processing and r2cv = 0.677, r2pred = 0.591 for 3‘-strand transfer).

VMNS2e is a novel biphenyl compound, which in previous studies had showed most favourable interactions with the active site of protein tyrosine phosphatase 1B (PTP1B). The effect of acute and chronic treatment of VMNS2e (30 mg/kg) was investigated in ob/ob mice. Plasma glucose was measured after acute administration of VMNS2e (30 mg/kg) in both lean and ob/ob mice. In the chronic study, VMNS2e (30 mg/kg) was given orally, once daily for 60 days. Metformin (300 mg/kg) was taken as standard therapy. Body weight, food intake and blood glucose was measured weekly while glycosylated hemoglobin A1c (HbA1c), insulin, triglyceride, total cholesterol, low density lipoprotein (LDL), fructosamine, non esterified fatty acid and organ weight were estimated after the completion of treatment period. Oral glucose tolerance test was performed on the last day of treatment. Liver and epididymal fat weights were taken. Acute dose of VMNS2e elicited an anti hyperglycemic effect. It reduced blood glucose by 14% (0.5 h) and 35.6% (6 h). Chronic VMNS2e treatment improved glucose tolerance by 25.3%. It decreased blood glucose levels. Hyperinsulinemia was reduced (19.6%). VMNS2e treatment had no significant effect on body weight and food consumption. VMNS2e treatment exhibited significant reduction (28.2%) in HbA1c, plasma triglyceride (49%), LDL (24%) and fructosamine (13%) levels. VMNS2e treatment did not alter total cholesterol and non esterified fatty acid levels. Epididymal fat/body weight ratio was reduced (26.3%). VMNS2e exhibited both acute and chronic anti hyperglycemic effect, insulin sensitivity along with improvement in various lipid parameters and glycemic control.

Histone deacetylases (HDACs) play a critical role in gene transcription and are implicated in cancer therapy and other diseases. Inhibitors of HDACs induce cell differentiation and suppress cell proliferation in the tumor cells. Although many such inhibitors have been designed and synthesized, but selective inhibitors for HDAC isoforms are lacking. Various hydroxamic acid analogues have been reported as HDAC inhibitors. Here, we report a three-dimensional quantitative structure-activity relationship (3D-QSAR) study performed using genetic function approximation (GFA) for this class of molecules. QSAR models were generated using a training set of 39 molecules and the predictive ability of final model was assessed using a test set of 17 molecules. The internal consistency of the final QSAR model was 0.712 and showed good external predictivity of 0.585. The results of the present QSAR study indicated that molecular shape analysis (MSA). thermodynamic and structural descriptors are important for inhibition of HDACs.

A new class of 4'-methylbiphenyl-2-(substituted phenyl)carboxamide derivatives had been previously evaluated in vivo for their anti-inflammatory activities in animal models of inflammation. In the present study, the most active compound of that series, compound 4e (4'-methylbiphenyl-2-(4-carboxy phenyl)carboxamide), was investigated in detail for its anti-inflammatory, analgesic and ulcerogenic potential. Pretreatment of rats with 4e (100 mg/kg) reduced carrageenan induced rat paw edema at 3 h compared to control group. Dose dependent percent inhibition of granuloma formation, exudate volume, total leukocyte count was observed in 4e (25, 50 and 100 mg/kg) and celecoxib (CAS 169590-42-5; 5 mg/kg) treated groups in the cotton pellet granuloma and granuloma pouch technique, respectively, in rats. C-reactive proteins were absent in the 4e treated group. Compound 4e inhibited acetic acid induced writhing dose dependently (10, 20 and 30 mg/kg). Compound 4e was inactive in the hot plate test. Gastric toxicity screening experiments showed that compound 4e, both after single and repeated oral administration, is devoid of any gastric irritation in rats. The LD 50 was found to be more than 2000 mg/kg.

Existing AIDS therapies are out of reach for most HIV-infected people in developing countries and, where available, they are limited by their toxicity and their cost. New anti-HIV agents are needed urgently to combat emerging viral resistance and reduce the side effects associated with currently available drugs. Toward this end, LeapFrog, a de novo drug design program was used to design novel, potent, and selective inhibitors of HIV-1 integrase. The designed compounds were synthesized and tested for in vitro inhibition of HIV-1 integrase. Out of the 25 compounds that were designed, and synthesized, four molecules (compounds 23, 26, 43, and 59) showed moderate to low inhibition of HIV-1 integrase for 3'-processing and 3'-strand transfer activities. Nonetheless, these compounds possess structural features not seen in known HIV-1 integrase inhibitors and thus can serve as excellent leads for further optimization of anti-HIV-1 integrase activity.

A homology model of Mycobacterium avium complex dihydrofolate reductase (MAC DHFR) was constructed on the basis of the X-ray crystal structure of Mycobacterium tuberculosis (Mtb) DHFR. The homology searching of the MAC DHFR resulted in the identification of the Mtb DHFR structure (PDB 1DF7) as the template for the model building. The MAC enzyme sequence was aligned to that of the Mtb counterpart using a modified Needleman and Wunsch methodology. The initial geometry to be modeled was copied from the template, either fully or partially depending on whether the residues were conserved or not, respectively. Using a randomized modeling procedure, 10 independent models of the target protein were built. The cartesian average of all the model structures was then refined using molecular mechanics. The resulting model was assessed for stereochemical quality using a Ramachandran plot and by analyzing the consistency of the model with the experimental data. The structurally and functionally important residues were identified from the model. Further, 5-deazapteridines recently reported as inhibitors of MAC DHFR were docked into the active site of the developed model. All the seven inhibitors used in the docking study have a similar docking mode at the active site. The network of hydrogen bonds around the 2,4-diamino-5-deazapteridine ring was found to be crucial for the binding of the inhibitors with the active site residues. The 5-methyl group of the inhibitors was located in a narrow hydrophobic pocket at the bottom of the active site. The relative values of the three torsion angles of the inhibitors were found to be important for the proper orientation of the inhibitor functional groups into the active site.

Rational approaches involving drug discovery technologies such as computational and combinatorial chemistry and high throughput screening have been useful tools to design and discover new drugs more efficiently. The interplay among structure-activity relationships, computer modelling, chemical synthesis and pharmacological testing can lead to better products for a particular therapeutic purpose. The work presented in this paper reports an example of successful application of computer-aided drug design method to find new azole antifungal agents. The designed compounds have been synthesized in the laboratory and tested for antifungal activity against Candida albicans ATCC 24433 in vitro. Two compounds exhibit good activity in vitro, which can be optimized for better activity.