Fluorine-a small magic bullet atom in the drug development: perspective to FDA approved and COVID-19 recommended drugs.

During the last twenty years, organic fluorination chemistry established itself as an important tool to get a biologically active compound. This belief can be supported by the fact that every year, we are getting fluorinated drugs in the market in extremely significant numbers. Last year, also ten fluorinated drugs have been approved by FDA and during the COVID-19 pandemic, fluorinated drugs played a very crucial role to control the disease and saved many lives. In this review, we surveyed all ten fluorinated drugs approved by FDA in 2021 and all fluorinated drugs which were directly-indirectly used during the COVID-19 period, and emphasis has been given particularly to their synthesis, medicinal chemistry, and development process. Out of ten approved drugs, one drug pylarify, a radioactive diagnostic agent for cancer was approved for use in positron emission tomography imaging. Also, very briefly outlined the significance of fluorinated drugs through their physical, and chemical properties and their effect on drug development.

Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach.

BACKGROUND & OBJECTIVES: Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. METHODS: Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. RESULTS: The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having better binding affinity compared to the PDB bound inhibitor of falcipain-III. The docking simulation results of falcipain-III with designed leupeptin analogues using Glide compared with AutoDock and find 80% similarity as better binder than leupeptin. INTERPRETATION & CONCLUSION: These results further highlight new leupeptin analogues as promising future inhibitors for chemotherapeutic prevention of malaria. The result of Glide for falcipain-III has been compared with the result of AutoDock and finds very less differences in their order of binding affinity. Although there are no extra hydrogen bonds, however, equal number of hydrogen bonds with variable strength as compared to leupeptin along with the enhanced hydrophobic and electrostatic interactions in case of analogues supports our study that it holds the ligand molecules strongly within the receptor. The comparative e-pharmacophoric study also suggests and supports our predictions regarding the minimum features required in ligand molecule to behave as falcipain- III inhibitors and is also helpful in screening the large database as future antimalarial inhibitors.

Physicochemical parameters for design and development of lead herbicide molecules: Is 'Lipinski's rule of 5' appropriate for herbicide discovery?

BACKGROUND: Herbicide use has been a great add-on in agriculture, aiding weed management in crop fields, thereby escalating crop production. However, the development of resistance in weeds against the existing herbicides is a setback. The development of herbicide resistance has compelled the agrochemical industries to replace existing herbicides with novel agrochemicals. Developing new herbicide molecules through traditional methods is time-consuming and cost-prohibitive. The use of high-throughput virtual screening (HTVS) through physicochemical properties, de novo design and combinatorial design of molecules with cutting-edge computational methods is an alternative to the traditional techniques in lead molecule discovery. The lack of optimal physicochemical criteria for screening herbicide-like molecules has become a hindrance in the process. RESULTS: In this study, physicochemical parameters [molecular weight, aromatic atoms, rotatable bonds, hydrogen-bonding capacity, topological polar surface area (TPSA), polarity and solubility] of known herbicide molecules have been studied and evaluated, and optimal criteria have been proposed for target-specific herbicides. Properties including molecular weight and hydrogen (H)-bond acceptor atoms tend to have higher values, but the range of H-bond donor atoms is relatively lower. These are distinguishable characteristics in herbicides when compared with oral drugs. Significant variations in optimal physicochemical parameters between herbicides of different groups (targeting weeds with different modes of action) have been observed. CONCLUSION: The proposed parameters for respective target sites could be used as filters for in silico screening, designing and developing of target-specific lead herbicide molecules. © 2023 Society of Chemical Industry.

Flap sub-domain dynamics of serine-threonine phosphatase (Stp1) of Staphylococcus aureus: an accelerated molecular dynamics simulation study.

Vancomycin and daptomycin are commonly used glycopeptide antibiotics to cure Gram-positive staphylococcal infections. The clinical isolates of mutant Staphylococcus aureus strains, Methicillin-Resistant (MRSA) and Vancomycin-Resistant (VRSA), have developed resistance against these antibiotics. A recently discovered Serine/threonine phosphatase (Stp1) is an Mn+2 containing protein at the active site with a flap sub-domain that participates in the phospho-signaling system of bacterial cell wall formation. The flap sub-domain probably regulates substrates recruitment and release with an extra Mn+2, possibly highly flexible as in the other homologous family of proteins. In this study, the flap sub-domain has been sampled with conventional and accelerated molecular dynamics (cMD and aMD) simulations to get other sub-optimal conformational states of the protein that are nearly impossible to observe through experimental methods. Trajectory analysis has shown that protein remained static in cMD while dynamic in aMD with RMSD of ∼2Å and ∼3Å, respectively. Accelerated MD has shown greater flexibility of ∼4 Å in the flap sub-domain, while cMD only captured a deviation of ∼ 2 Å. Later, the dynamic cross-correlation map (DCCM) confirmed that the flap sub-domain is significantly more flexible than the other part of the structure, indicating its role in substrate regulation. Secondary structure transition in the flap sub-domain, i.e. 3-10 helix and turn (PRO159 - ILE163) region of the flap sub-domain shifted into α-helix, which is a more stable structure. Further, the trajectory has been clustered, and conformational states extracted, which may be exploited in structure-based antibiotics discovery.Communicated by Ramaswamy H. Sarma.

Computational evaluation of phytochemicals targeting DNA topoisomerase I in Leishmania donovani: molecular docking and molecular dynamics simulation studies.

DNA topoisomerase I (Topo I) is a ubiquitous enzyme that plays a crucial role in resolving the topological constraints of supercoiled DNA during various cellular activities, including repair, replication, recombination, transcription, and chromatin remodeling. Multiple studies have confirmed the essential role of Topo I in nucleic acid metabolism of Leishmania donovani, the kinetoplastid parasite responsible for visceral leishmaniasis or kala-azar. Inhibition of this enzyme has shown promise as a strategy for therapy against visceral leishmaniasis. However, current treatment options suffer from limitations related to effectiveness, cost, and side effects. To address these challenges, computational methods have been employed in this study to investigate the inhibition of Leishmania donovani DNA topoisomerase I (LdTopo I) by phytochemicals derived from Indian medicinal plants known for their anti-leishmanial activity. A library of phytochemicals and known inhibitors was assembled, and virtual screening based on docking binding affinities was conducted to identify potent phytochemical inhibitors. To assess the drug-likeness of the docked phytochemicals, their physicochemical properties were predicted. Additionally, molecular dynamics (MD) simulations were performed on the docked complexes for a duration of 100 ns to evaluate their stability, intermolecular interactions, and dynamic behavior. Among all the docked phytochemicals, three compounds, namely CID23266147 (withanolide N), CID5488537 (fagopyrine), and CID100947536 (isozeylanone), exhibited the highest inhibitory potential against LdTopo I. These findings hold promise for the development of novel inhibitors targeting LdTopo I, which could potentially lead to improved therapies for visceral leishmaniasis.Communicated by Ramaswamy H. Sarma.

6-Ethoxy-4- N-(2-morpholin-4-ylethyl) -2-N-propan-2-yl-1,3, 5-triazine-2, 4-diamine endows herbicidal activity against Phalaris minor a weed of wheat crop field: An in -silico and experimental approaches of herbicide discovery.

Phalaris minor is a major weed of wheat crop which has evolved resistance against herbicides. Isoproturon is the most accepted herbicide developed resistance in 1992. Later, introduced herbicides also developed resistance and cross-resistance to their respective binding sites. Isoproturon binds at the QB binding site of the D1 protein of photosystem-II (PS-II), which blocks the electron transfer in photosynthesis. In this work, we have carried out a series of computational studies to prioritize the promising herbicides against D1 protein of P. minor. Through the computational studies, twenty-four lead molecules are prioritized which have shown a higher binding affinity and inhibition constant than the reference ligand molecule. The binding and conformational stability of docked complexes was evaluated by molecular dynamics simulations and binding free energy calculations i.e., MM/PBSA. A list of amino acids such as Ala225, Ser226, Phe227, and Asn229 present in the binding site of protein is obtained to be playing an important role in the stability of the protein-lead complex via hydrogen bond and π-π interactions. Binding free energy calculation revealed that the selected lead molecule binding is energetically favorable and driven by electrostatic interactions. Among 24 leads, computational results have uncovered eight promising compounds as potential herbicides which have shown comparable physiochemical profile, better docking scores, system stability, H-bond occupancy, and binding free energy than terbutryn, a reference molecule. These prioritized molecules were custom synthesized and evaluated for their herbicidal activity and specificity through whole plant assay under laboratory-controlled conditions. The lead molecule ELC5 (6-ethoxy-4-N-(2-morpholin-4-ylethyl)-2-N-propan-2-yl-1,3,5-triazine-2,4-diamine) has shown comparable activity to the reference herbicide(isoproturon) against P. minor.

Sequence and structural similarities of ACCase protein of Phalaris minor and wheat: An insight to explain herbicide selectivity.

Uncontrolled growth of Phalaris minor in the wheat (Triticum aestivum) crop has remained a problem, leading to a massive reduction in wheat grain production. Herbicides have been used to control the weed, which leads to the development of frequent resistance in P. minor and mutant biotypes were also reported (Trp2027Cys and Ile2041Asn). Development of resistance enforced agro researchers to analyses the action of herbicide on P. minor. In this study, the sequence and structure of P. minor and T. aestivum Acetyl CoA Carboxylase (ACCase) have been analysed to locate the differences in their sequence and structure and to formulate a plausible explanation of the selectivity of herbicides which may help in the rationale discovery of noble herbicides. The sequence and 3D structure analysis of weed and wheat ACCase indicate minute differences in the distantly located amino acid residues. However, proteins are conserved at the binding site of herbicides with no mutation at the catalytic site. Analysis indicates that herbicides selectively target P. minor ACCase might be due to unknown other reasons, but not due to differences in their protein sequence and structure.

S-adenosyl-L-homocysteine Hydrolase: Its Inhibitory Activity Against Plasmodium falciparum and Development of Malaria Drugs.

Parasite Plasmodium falciparum is continuously giving a challenge to human beings by changing itself against most of the antimalarial drugs and its consequences can be seen in the form of a huge number of deaths each year especially in the poor and developing country. Due to its drug resistance ability, new drugs are regularly needed to kill the organism. Many new drugs have been developed based on different mechanisms. One of the potential mechanisms is to hamper protein synthesis by blocking the gene expression. S-Adenosyl-L-homocysteine (SAH) hydrolase is a NAD+ dependent tetrameric enzyme, which is responsible for the reversible hydrolysis of AdoHcy to adenosine and L-homocysteine, has been recognized as a new target for antimalarial agents since the parasite has a specific SAH hydrolase. The inhibition of SAH hydrolase causes the intracellular accumulation of S-Adenosyl-L-homocysteine, elevating the ratio of SAH to S-adenosylmethionine (SAM) and inhibiting SAM-dependent methyltransferase that catalyzes methylation of the capped structure at the 5'-terminus of mRNA, and other methylation reaction which is essential for parasite proliferation. In other words, S-Adenosyl-Lhomocysteine hydrolase regulates methyltransferase reactions. In this way, SAH hydrolase inhibitors can be used for the treatment of different diseases like malaria, cancer, viral infection, etc. by ultimately stopping the synthesis of protein. Many antiviral drugs have been synthesized and marketed which are based on the inhibition of SAH hydrolase. This review summarises the development of SAH inhibitors developed over the last 20 years and their potentiality for the treatment of malaria.

Structural elucidation of transmembrane domain zero (TMD0) of EcdL: A multidrug resistance-associated protein (MRP) family of ATP-binding cassette transporter protein revealed by atomistic simulation.

ATP-Binding cassette (ABC) transporters play an extensive role in the translocation of diverse sets of biologically important molecules across membrane. EchnocandinB (antifungal) and EcdL protein of Aspergillus rugulosus are encoded by the same cluster of genes. Co-expression of EcdL and echinocandinB reflects tightly linked biological functions. EcdL belongs to Multidrug Resistance associated Protein (MRP) subfamily of ABC transporters with an extra transmembrane domain zero (TMD0). Complete structure of MRP subfamily comprising of TMD0 domain, at atomic resolution is not known. We hypothesized that the transportation of echonocandinB is mediated via EcdL protein. Henceforth, it is pertinent to know the topological arrangement of TMD0, with other domains of protein and its possible role in transportation of echinocandinB. Absence of effective template for TMD0 domain lead us to model by I-TASSER, further structure has been refined by multiple template modelling using homologous templates of remaining domains (TMD1, NBD1, TMD2, NBD2). The modelled structure has been validated for packing, folding and stereochemical properties. MD simulation for 0.1 µs has been carried out in the biphasic environment for refinement of modelled protein. Non-redundant structures have been excavated by clustering of MD trajectory. The structural alignment of modelled structure has shown Z-score -37.9; 31.6, 31.5 with RMSD; 2.4, 4.2, 4.8 with ABC transporters; PDB ID 4F4C, 4M1 M, 4M2T, respectively, reflecting the correctness of structure. EchinocandinB has been docked to the modelled as well as to the clustered structures, which reveals interaction of echinocandinB with TMD0 and other TM helices in the translocation path build of TMDs.

In silico modelling and molecular dynamics simulation studies of thiazolidine based PTP1B inhibitors.

Protein tyrosine phosphatase 1B (PTP1B) has been identified as a negative regulator of insulin and leptin signalling pathway; hence, it can be considered as a new therapeutic target of intervention for the treatment of type 2 diabetes. Inhibition of this molecular target takes care of both diabetes and obesity, i.e. diabestiy. In order to get more information on identification and optimization of lead, pharmacophore modelling, atom-based 3D QSAR, docking and molecular dynamics studies were carried out on a set of ligands containing thiazolidine scaffold. A six-point pharmacophore model consisting of three hydrogen bond acceptor (A), one negative ionic (N) and two aromatic rings (R) with discrete geometries as pharmacophoric features were developed for a predictive 3D QSAR model. The probable binding conformation of the ligands within the active site was studied through molecular docking. The molecular interactions and the structural features responsible for PTP1B inhibition and selectivity were further supplemented by molecular dynamics simulation study for a time scale of 30 ns. The present investigation has identified some of the indispensible structural features of thiazolidine analogues which can further be explored to optimize PTP1B inhibitors.

A Spectroscopic and Molecular Simulation Approach toward the Binding Affinity between Lysozyme and Phenazinium Dyes: An Effect on Protein Conformation.

A comparative study of binding interaction between Safranin O (SO) and Neutral Red (NR) with lysozyme (Lyz) has been reported using several spectroscopic methods along with computational approaches. Steady-state fluorescence measurements revealed static quenching as the major quenching mechanism in Lyz-SO and Lyz-NR interaction, which is further supported by time-resolved fluorescence and UV-vis measurements. Additionally, binding and thermodynamic parameters of these interactions are calculated from temperature dependent fluorescence data. Moreover, conformational changes of protein upon binding with SO and NR are provided by synchronous and circular dichroism (CD) measurements. Molecular docking study provided the exact binding location of SO and NR in lysozyme. Along with this study, molecular dynamics simulation is carried out to measure the stability of Lyz, Lyz-SO, and Lyz-NR complex. The present study revealed the strong binding affinity of dyes with lysozyme, and this study would be helpful toward medical and environmental science.

Study of interaction of human serum albumin with curcumin by NMR and docking.

Curcumin has been reported to be therapeutically active but has poor bioavailability, half life, and high rate of metabolic detoxifcation. Most of the hydrophobic and acidic drugs get transported through human serum albumin (HSA). Binding of drugs to serum protein increases their half-life. The present study is focused to analyze interaction of curcumin with HSA by NMR and docking studies. In order to investigate the binding affinity of curcumin with HSA, NMR based diffusion techniques and docking study have been carried out. We report that curcumin has shown comparable binding affinity value vis-a-vis standard, the accessible surface area (ASA) of human serum albumin (uncomplexed) and its docked complex with curcumin at both binding sites was calculated and found to be close to that of warfarin and diazepam respectively. Conclusion drawn from our study demonstrates that curcumin interacts with HSA strongly thereby its poor half life is due to high rate of its metabolic detoxification as reported in literature.

A plausible explanation for enhanced bioavailability of P-gp substrates in presence of piperine: simulation for next generation of P-gp inhibitors.

P-glycoprotein (P-gp) has a major role to play in drug pharmacokinetics and pharmacodynamics, since it effluxes many cytotoxic hydrophobic anticancer drugs from gastrointestinal tract, brain, liver and kidney. Piperine is known to enhance the bioavailability of curcumin, as a substrate of P-gp by at least 2000%. Besides these at least 50 other substrates and inhibitors of P-gp have been reported so far. All P-gp inhibitors have diverse structures. Although little is known about binding of some flavonoids and steroids at the NBD (nucleotide binding domain) of P-gp in the vicinity of ATP binding site inhibiting its hydrolysis, a valid explanation of how P-gp accommodates such a diverse set of inhibitors is still awaited. In the present study, piperine up to 100 µM has not shown observable cytotoxic effect on MDCK cell line, and it has been shown to accumulate rhodamine by fluorescence microscopy and fluorescent activated cell sorter in MDCK cells. Computational simulation for piperine and some first and second generation P-gp inhibitors has shown that these dock at the NBD site of P-gp. A comparative simulation study has been carried out regarding their docking and binding energies. Binding conformation of P-gp co-crystallized complexes with ADP, AMP-PNP (Adenylyl-imidodiphosphate), and ATP were compared with piperine. The receptor based E-pharmacophore of docked piperine has been simulated to find common features amongst P-gp inhibitors. Finally it has been concluded that piperine could be utilized as base molecule for design and development of safe non-toxic inhibitor of P-gp in order to enhance the bioavailability of most of its substrates.

3D QSAR and pharmacophore study of curcuminoids and curcumin analogs: interaction with thioredoxin reductase.

Curcumin is the yellow pigment of Curcuma longa that irreversibly inhibits the activity of thioredoxin reductase (TrxR) and forms adduct. TrxR, a homodimeric enzyme with E and F chains, is responsible for redox control of the cell and defense against oxidative stress. It is also well known that TrxR is over-expressed in tumor cells. Hence TrxR is a promising target for curcumin based therapy. Binding site of TrxR for curcumin is at the interface of homodimers. In the present study, naturally occurring curcuminoids and forty four synthetic analogs of curcumin were docked with SP/XP glide suite and E-pharmacophore was simulated. E-pharmacophore of both chains has shown three donor features and one acceptor feature. 3D atom based QSAR models have been proposed for the two series of curcumin analogues of known IC50values. The data obtained indicates that the training set model is quite efficient to predict the test set of data. Obtained models and ADMET prediction could be employed for design and synthesis of more potent inhibitors of TrxR.

Docking and in silico ADMET studies of noraristeromycin, curcumin and its derivatives with Plasmodium falciparum SAH hydrolase: a molecular drug target against malaria.

The Plasmodium falciparum S-adenosyl-L-homocysteine hydrolase (pfSAHH) enzyme has been considered as a potential chemotherapeutic target against malaria due to the amino acid differences found on binding sites of pfSAHH related to human SAHH. It has been reported that noraristeromycin and some curcumin derivatives have potential binding with the largest cavity of pfSAHH, which is also related to the binding with Nicotinamide-Adenine-Dinucleotide (NAD) and Adenosine (ADN). Our present work focuses on docking and ADMET studies to select potential inhibitors of pfSAHH. The binding of the selected inhibitor of the PfSAHH active site was analyzed using Molegro Virtual Docker. In this study, curcumin and its derivatives have been found to have higher binding affinity with pfSAHH than noraristeromycin. Seven amino acid residues Leu53, His54, Thr56, Lys230, Gly397, His398 and Phe407 of pfSAHH involved in binding with curcumin, are the same as those for noraristeromycin, which reveals that curcumin and noraristeromycin bind in the same region of pfSAHH. Curcumin has shown a strong interaction with hydrophobic amino acid residues of pfSAHH. Molecular Docking and ADMET predictions suggest that curcumin can be a potent inhibitor of pfSAHH with ability to modulate the target in comparatively smaller dose. Therefore, curcumin is likely to become a good lead molecule for the development of effective drug against malaria.

Curcumin conjugates induce apoptosis via a mitochondrion dependent pathway in MCF-7 and MDA-MB-231 cell lines.

In order to enhance the bioavailability of curcumin its conjugates with piperic acid and glycine were synthesized by esterifying the 4 and 4' phenolic hydroxyls, the sites of metabolic conjugation. Antiproliferative and apoptotic efficacy of synthesized conjugates was investigated in MCF-7 and MDA-MB-231 cell lines. IC50 values of di-O-glycinoyl (CDG) and di-O-piperoyl (CDP) esters of curcumin were found to be comparable with that of curcumin. Both conjugates induced chromatin condensation fragmentation and apoptotic body formation. CDP exposure to MCF-7 cells induced apoptosis initiating loss of mitochondrial membrane potential (Δψm) followed by inhibition of translocation of transcription factor NF-kB and release of Cytochrome-C. Reactive oxygen species (ROS) production was evaluated by fluorescent activated cell sorter. Change in ratio of Bcl2/ Bclxl was observed, suggesting permeablization of mitochondrial membrane leading to the release of AIF, Smac and other apoptogenic molecules. DNA fragmentation as a hallmark for apoptosis was monitored by TUNEL as well as agrose gel electrophoresis. Thus, it was proven that conjugation does not affect the therapeutic potential of parent molecule in vitro, while these could work in vivo as prodrugs with enhanced pharmacokinetic profile. Pharmacokinetics of these molecules under in vivo conditions is a further scope of this study.

Mechanism of isoproturon resistance in Phalaris minor: in silico design, synthesis and testing of some novel herbicides for regaining sensitivity.

Isoproturon, 3-p-cumenyl-1 dimethylurea was the only herbicide controlling Phalaris minor, a major weed growing in wheat fields till the early 1980s. Since it has acquired resistance against isoproturon, like other substituted urea herbicides, where the identified target site for isoproturon is in the photosynthetic apparatus at D1 protein of Photosystem-II (PS-II). Nucleotide sequence of susceptible and resistant psbA gene of P. minor has been reported to have four point mutations. During the present work D1 protein of both susceptible and resistant biotypes of P Minor has been modeled. Transmembrane segments of amino acids were predicted by comparing with the nearest homolog of bacterial D1 protein. Volume and area of active site of both susceptible and resistant biotypes has been simulated. Isoproturon was docked at the active site of both, susceptible and resistant D1 proteins. Modeling and simulation of resistance D1 protein indicates that the resistance is due to alteration in secondary structure near the binding site, resulting in loss in cavity area, volume and change in binding position, loss of hydrogen bonds, hydrophobic interaction and complete loss of hydrophobic sites. To regain sensitivity in resistant biotype new derivatives of isoproturon molecules have been proposed, synthesized and tested. Among the 17 derivatives we found that the N-methyl triazole substituted isoproturon is a potential substitute for isoproturon.

Molecular modeling and computational simulation of the photosystem-II reaction center to address isoproturon resistance in Phalaris minor.

Isoproturon is the only herbicide that can control Phalaris minor, a competitive weed of wheat that developed resistance in 1992. Resistance against isoproturon was reported to be due to a mutation in the psbA gene that encodes the isoproturon-binding D1 protein. Previously in our laboratory, a triazole derivative of isoproturon (TDI) was synthesized and found to be active against both susceptible and resistant biotypes at 0.5 kg/ha but has shown poor specificity. In the present study, both susceptible D1((S)), resistant D1((R)) and D2 proteins of the PS-II reaction center of P. minor have been modeled and simulated, selecting the crystal structure of PS-II from Thermosynechococcus elongatus (2AXT.pdb) as template. Loop regions were refined, and the complete reaction center D1/D2 was simulated with GROMACS in lipid (1-palmitoyl-2-oleoylglycero-3-phosphoglycerol, POPG) environment along with ligands and cofactor. Both S and R models were energy minimized using steepest decent equilibrated with isotropic pressure coupling and temperature coupling using a Berendsen protocol, and subjected to 1,000 ps of MD simulation. As a result of MD simulation, the best model obtained in lipid environment had five chlorophylls, two plastoquinones, two phenophytins and a bicarbonate ion along with cofactor Fe and oxygen evolving center (OEC). The triazole derivative of isoproturon was used as lead molecule for docking. The best worked out conformation of TDI was chosen for receptor-based de novo ligand design. In silico designed molecules were screened and, as a result, only those molecules that show higher docking and binding energies in comparison to isoproturon and its triazole derivative were proposed for synthesis in order to get more potent, non-resistant and more selective TDI analogs.

Plant polyphenols as electron donors for erythrocyte plasma membrane redox system: validation through in silico approach.

BACKGROUND: The plasma membrane redox system (PMRS) has extensively been studied in erythrocytes. The PMRS plays an important role in maintaining plasma redox balance and provides a protective mechanism against oxidative stress. Earlier it was proposed that only NADH or NADPH provided reducing equivalents to PMRS; however, now it is acknowledged that some polyphenols also have the ability to donate reducing equivalents to PMRS. METHODS: Two different docking simulation softwares, Molegro Virtual Docker and Glide were used to study the interaction of certain plant polyphenols viz. quercetin, epigallocatechin gallate, catechin epicatechin and resveratrol with human erythroyte NADH-cytochrome b5 reductase, which is a component of PMRS and together with the identification of minimum pharmacophoric feature using Pharmagist. RESULTS: The derived common minimum pharmacophoric features show the presence of minimum bioactive component in all the selected polyphenols. Our results confirm wet lab findings which show that these polyphenols have the ability to interact and donate protons to the Human NADH-cytochrome b5 reductase. CONCLUSION: With the help of these comparative results of docking simulation and pharmacophoric features, novel potent molecules can be designed with higher efficacy for activation of the PMRS system.

Curcuminoids as inhibitors of thioredoxin reductase: a receptor based pharmacophore study with distance mapping of the active site.

Curcumin is the yellow pigment of turmeric that interacts irreversibly forming an adduct with thioredoxin reductase (TrxR), an enzyme responsible for redox control of cell and defence against oxidative stress. Docking at both the active sites of TrxR was performed to compare the potency of three naturally occurring curcuminoids, namely curcumin, demethoxy curcumin and bis-demethoxy curcumin. Results show that active sites of TrxR occur at the junction of E and F chains. Volume and area of both cavities is predicted. It has been concluded by distance mapping of the most active conformations that Se atom of catalytic residue SeCYS498, is at a distance of 3.56 from C13 of demethoxy curcumin at the E chain active site, whereas C13 carbon atom forms adduct with Se atom of SeCys 498. We report that at least one methoxy group in curcuminoids is necessary for interation with catalytic residues of thioredoxin. Pharmacophore of both active sites of the TrxR receptor for curcumin and demethoxy curcumin molecules has been drawn and proposed for design and synthesis of most probable potent antiproliferative synthetic drugs.