Comprehensive structural analysis of the open and closed conformations of Theileria annulata enolase by molecular modelling and docking

Theileria annulata is an apicomplexan parasite which is responsible for tropical theileriosis in cattle. Due to resistance of T. annulata against commonly used antitheilerial drug, new drug candidates should be identified urgently. Enolase might be a druggable protein candidate which has an important role in glycolysis, and could also be related to several cellular functions as a moonlight protein. In this study; we have described three-dimensional models of open and closed conformations of T. annulata enolase by homology modeling method for the first time with the comprehensive domain, active site and docking analyses. Our results show that the enolase has similar folding patterns within enolase superfamily with conserved catalytic loops and active site residues. We have described specific insertions, possible plasminogen binding sites, electrostatic potential surfaces and positively charged pockets as druggable regions in T. annulata enolase.     

Doxycycline Interferes with Zika Virus Serine Protease and Inhibits Virus Replication in Human Skin Fibroblasts

Zika virus (ZIKV) represents a re-emerging threat to global health due to its association with congenital birth defects. ZIKV NS2B-NS3 protease is crucial for virus replication by cleaving viral polyprotein at various junctions to release viral proteins and cause cytotoxic effects in ZIKV-infected cells. This study characterized the inhibitory effects of doxycycline against ZIKV NS2B-NS3 protease and viral replication in human skin cells. The in silico data showed that doxycycline binds to the active site of ZIKV protease at a low docking energy (−7.8 Kcal/mol) via four hydrogen bonds with the protease residues TYR1130, SER1135, GLY1151, and ASP83. Doxycycline efficiently inhibited viral NS2B-NS3 protease at average human temperature (37 °C) and human temperature with a high fever during virus infection (40 °C). Interestingly, doxycycline showed a higher inhibitory effect at 40 °C (IC50 = 5.3 µM) compared to 37 °C (9.9 µM). The virus replication was considerably reduced by increasing the concentration of doxycycline. An approximately 50% reduction in virus replication was observed at 20 µM of doxycycline. Treatment with 20 µM of doxycycline reduced the cytopathic effects (CPE), and the 40 µM of doxycycline almost eliminated the CPE of human skin cells. This study showed that doxycycline binds to the ZIKV protease and inhibits its catalytic activity at a low micro-molecular concentration range. Treatment of human skin fibroblast with doxycycline eliminated ZIKV infection and protected the cells against the cytopathic effects of the infection.     

Molecular docking revealed the binding of nucleotide/side inhibitors to Zika viral polymerase solved structures

A new Zika virus (ZIKV) outbreak started in 2015. According to the World Health Organization, 84 countries confirmed ZIKV infection. RNA-dependent RNA polymerase (RdRp) was an appealing target for drug designers during the last two decades. Through molecular docking, we screened 16 nucleotide/side inhibitors against ZIKV RdRp. While the mode of interaction with ZIKV is different from that in the hepatitis C virus (HCV), nucleotide/side inhibitors in this study (mostly anti-HCV) showed promising binding affinities (?6.2 to ?9.7 kcal/mol calculated by AutoDock Vina) to ZIKV RdRp. Setrobuvir, YAK and, to a lesser extent, IDX-184 reveal promising results compared to other inhibitors in terms of binding ZIKV RdRp. These candidates would be powerful anti-ZIKV drugs.     

Designing anti-Zika virus peptides derived from predicted human-Zika virus protein-protein interactions

The production of anti-Zika virus (ZIKV) therapeutics has become increasingly important as the propagation of the devastating virus continues largely unchecked. Notably, a causal relationship between ZIKV infection and neurodevelopmental abnormalities has been widely reported, yet a specific mechanism underlying impaired neurological development has not been identified. Here, we report on the design of several synthetic competitive inhibitory peptides against key pathogenic ZIKV proteins through the prediction of protein–protein interactions (PPIs). Often, PPIs between host and viral proteins are crucial for infection and pathogenesis, making them attractive targets for therapeutics. Using two complementary sequence-based PPI prediction tools, we first produced a comprehensive map of predicted human-ZIKV PPIs (involving 209 human protein candidates). We then designed several peptides intended to disrupt the corresponding host-pathogen interactions thereby acting as anti-ZIKV therapeutics. The data generated in this study constitute a foundational resource to aid in the multi-disciplinary effort to combat ZIKV infection, including the design of additional synthetic proteins.     

Comparative protein modeling of 1-deoxy-D-xylulose-5-phosphate reductoisomerase enzyme from Plasmodium falciparum: a potential target for antimalarial drug discovery

Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Pf-DXR) is a potential target for antimalarial chemotherapy. The three-dimensional model (3D) of this enzyme was determined by means of comparative modeling through multiple alignment followed by intensive optimization, minimization, and validation. The resulting model demonstrates a reasonable topology as gauged from the Ramachandran plot and acceptable three-dimensional structure compatibility as assessed by the Profiles-3D score. The modeled monomeric subunit consists of three domains: (1) N-terminal NADPH binding domain, (2) connective or linker domain (with most of the active site residues located in this domain), and (3) a C-terminal domain. This structure proved to be consistent with known DXR crystal structures from other species. The predicted active site compared favorably with those of the templates and appears to have an active site with a highly conserved architecture. Additionally, the model explains several site-directed mutagenesis data. Besides using several protein structure-checking programs to validate the model, a set of known inhibitors of DXR were also docked into the active site of the modeled Pf-DXR. The docked scores correlated reasonably well with experimental pIC50 values with a regression coefficient (R2) equal to 0.84. Results of the current study should prove useful in the early design and development of inhibitors by either de novo drug design or virtual screening of large small-molecule databases leading to development of new antimalarial agents.     

Targeting tribbles homolog 3 (TRIB3) protein against type 2 diabetes for the identification of potential inhibitors by in silico screening

Tribbles homolog 3 (TRIB3) protein is inhibiting the insulin signaling by directly binding to the Akt/PKB leading to insulin resistance in the pancreas causing type 2 diabetes mellitus. Hence, TRIB3 protein is considered as a possible drug target for the new lead identification against type 2 diabetes. In the present study, the homology model of TRIB3 protein was generated to explore its biochemical function and molecular interactions in the new lead identification. The energy minimization of TRIB3 protein was carried out and evaluated by validation protocols for structure reliability. The druggable binding site of TRIB3 protein was identified for the virtual screening and molecular docking studies. The Asinex-fragments library of 22634 small molecules was docked at TRIB3 active site using the Glide module to identify new chemical entities. A total of 9 molecules were identified as final hits from virtual screening and their potency was ranked using Glide score, Glide energies, and residues interactions. The 6 prioritized lead molecules were further optimized using AutoDock, Prime MM/GBSA, and percentage of human oral absorption for the identification of potential leads. The molecules L2, L5, and L6 are identified as lead inhibitors and are showing consistent interactions with key residues Glu194 and Lys196 of TRIB3 protein. The identified potential leads were analyzed by ADME properties for their drug likeness and HergIC50 values are predicted for the prevention of preclinical failures. The present work sheds light on the identification of the best lead molecules against TRIB3 protein and offers a route to design as novel potential drug candidates for T2DM.     

Probing key coordination interactions: configurationally restricted metal activated CXCR4 antagonists

The syntheses of configurationally restricted mono- and bis-macrocyclic copper(II) perchlorate complexes (copper(II) 5-benzyl-1,5,8,12-tetraazabicyclo[10.2.2]hexadecane and dicopper(II) 5,5'-[1,4-phenylenebis(methylene)]-bis(1,5,8,12-tetraazabicyclo[10.2.2]hexadecane)) are reported and the X-ray structure of the copper(II) mono-macrocyclic complex has been determined. EXAFS studies on the bis-macrocyclic species in aqueous solution show that the copper coordination spheres are essentially identical to the solid state structure, and do not vary in the presence of 20 equivalents of sodium acetate per metal centre. DFT calculations were carried out at the BP86/TZP level to determine the nature of potential binding interactions with CXCR4 aspartate residues. The alkylated single macrocyclic compound was modelled with an acetate included to represent the aspartate residue, demonstrating that the predicted macrocycle configuration has the lowest energy and the acetate interaction is effectively monodentate giving a distorted trigonal bipyramidal geometry at the copper centre. In vitro anti-HIV infection assays show that the configurationally restricted dicopper(II) complex is more active (average EC(50) = 0.026 microM against HIV-1) than the non-constrained dicopper(II) 1,1'-[1,4-phenylenebis(methylene)]-bis(1,4,8,11-tetraazacyclotetradecane) (average EC(50) = 0.047 microM against HIV-1) although it is an order of magnitude less active than the configurationally restricted dizinc(II) complex.     

In Silico Drug Repurposing Approach: Investigation of Mycobacterium tuberculosis FadD32 Targeted by FDA-Approved Drugs

Background: Despite the enormous efforts made towards combating tuberculosis (TB), the disease remains a major global threat. Hence, new drugs with novel mechanisms against TB are urgently needed. Fatty acid degradation protein D32 (FadD32) has been identified as a promising drug target against TB, the protein is required for the biosynthesis of mycolic acids, hence, essential for the growth and multiplication of the mycobacterium. However, the FadD32 mechanism upon the binding of FDA-approved drugs is not well established. Herein, we applied virtual screening (VS), molecular docking, and molecular dynamic (MD) simulation to identify potential FDA-approved drugs against FadD32. Methodology/Results: VS technique was found promising to identify four FDA-approved drugs (accolate, sorafenib, mefloquine, and loperamide) with higher molecular docking scores, ranging from −8.0 to −10.0 kcal/mol. Post-MD analysis showed that the accolate hit displayed the highest total binding energy of −45.13 kcal/mol. Results also showed that the accolate hit formed more interactions with FadD32 active site residues and all active site residues displayed an increase in total binding contribution. RMSD, RMSF, Rg, and DCCM analysis further supported that the presence of accolate exhibited more structural stability, lower bimolecular flexibility, and more compactness into the FadD32 protein. Conclusions: Our study revealed accolate as the best potential drug against FadD32, hence a prospective anti-TB drug in TB therapy. In addition, we believe that the approach presented in the current study will serve as a cornerstone to identifying new potential inhibitors against a wide range of biological targets.     

Discovery of Bispecific Lead Compounds from Azadirachta indica against ZIKA NS2B-NS3 Protease and NS5 RNA Dependent RNA Polymerase Using Molecular Simulations

Zika virus (ZIKV) has been characterized as one of many potential pathogens and placed under future epidemic outbreaks by the WHO. However, a lack of potential therapeutics can result in an uncontrolled pandemic as with other human pandemic viruses. Therefore, prioritized effective therapeutics development has been recommended against ZIKV. In this context, the present study adopted a strategy to explore the lead compounds from Azadirachta indica against ZIKV via concurrent inhibition of the NS2B-NS3 protease (ZIKV^pro) and NS5 RNA dependent RNA polymerase (ZIKV^RdRp) proteins using molecular simulations. Initially, structure-based virtual screening of 44 bioflavonoids reported in Azadirachta indica against the crystal structures of targeted ZIKV proteins resulted in the identification of the top four common bioflavonoids, viz. Rutin, Nicotiflorin, Isoquercitrin, and Hyperoside. These compounds showed substantial docking energy (−7.9 to −11.01 kcal/mol) and intermolecular interactions with essential residues of ZIKV^pro (B:His⁵¹, B:Asp⁷⁵, and B:Ser¹³⁵) and ZIKV^RdRp (Asp⁵⁴⁰, Ile⁷⁹⁹, and Asp⁶⁶⁵) by comparison to the reference compounds, O7N inhibitor (ZIKV^pro) and Sofosbuvir inhibitor (ZIKV^RdRp). Besides, long interval molecular dynamics simulation (500 ns) on the selected docked poses reveals stability of the respective docked poses contributed by intermolecular hydrogen bonds and hydrophobic interactions. The predicted complex stability was further supported by calculated end-point binding free energy using molecular mechanics generalized born surface area (MM/GBSA) method. Consequently, the identified common bioflavonoids are recommended as promising therapeutic inhibitors of ZIKV^pro and ZIKV^RdRp against ZIKV for further experimental assessment.     

Epitopes based drug design for dengue virus envelope protein: A computational approach

Dengue virus (DENV) has emerged as a rapidly spreading epidemic throughout the tropical and subtropical regions around the globe. No suitable drug has been designed yet to fight against DENV, therefore, the need for safe and effective antiviral drug has become imperative. The envelope protein of DENV is responsible for mediating the fusion process between viral and host membranes. This work reports an in silico approach to target B and T cell epitopes for dengue envelope protein inhibition. A conserved region “QHGTI” in B and T cell epitopes of dengue envelope glycoprotein was confirmed to be valid for targeting by visualizing its interactions with the host cell membrane TIM-1 protein which acts as a receptor for serotype 2 and 3. A reverse pharmacophore mapping approach was used to generate a seven featured pharmacophore model on the basis of predicted epitope. This pharmacophore model as a 3D query was used to virtually screen a chemical compounds dataset “Chembridge”. A total of 1010 compounds mapped on the developed pharmacophore model. These retrieved hits were subjected to filtering via Lipinski’s rule of five, as a result 442 molecules were shortlisted for further assessment using molecular docking. Finally, 14 hits of different structural properties having interactions with the active site residues of dengue envelope glycoprotein were selected as lead candidates. These structurally diverse lead candidates have strong likelihood to act as further starting structures in the development of novel and potential drugs for the treatment of dengue fever.     

In silico structure-based design of enhanced peptide inhibitors targeting RNA polymerase PAN-PB1C interaction

Developing antivirals for influenza A virus (FluA) has become more challenging due to high range of antigenic mutation and increasing numbers of drug-resistant viruses. Finding a selective inhibitor to target highly conserved region of protein-protein interactions interface, thereby increasing its efficiency against drug resistant virus could be highly beneficial. In this study, we used in silico approach to derive FluAPep1 from highly conserved region, PA_N-PB1_C interface and generated 121 FluAPep1 analogues. Interestingly, we found that the FluAPep1 interaction region in the PA_N domain are highly conserved in many FluA subtypes. Especially, FluAPep1 targets two pandemic FluA strains, H1N1/avian/2009 and H3N2/Victoria/1975. All of these FluA subtypes PA_N domain (H1N1/H3N2CAN/H3N2VIC/H7N1/H7N2) were superimposed with PA_N domain from H17N10 and the calculated root mean standards deviations were less than 3 Å. FlexPepDock analysis revealed that FluAPep1 exhibited higher binding affinity (score -246.155) with the PA_N domain. In addition, around 86% of non-hot spot mutated peptides (FluAPep28-122) showed enhanced binding affinity with PA_N domain. ToxinPred analysis confirmed that designed peptides were non-toxic. Thus, FluAPep1 and its analogues has potential to be further developed into an antiviral treatment against FluA infection.     

Bruguiera gymnorhiza (L.) Lam. at the Forefront of Pharma to Confront Zika Virus and Microbial Infections—An In Vitro and In Silico Perspective

The recent emergence of Zika virus (ZIKV) in Brazil and the increasing resistance developed by pathogenic bacteria to nearly all existing antibiotics should be taken as a wakeup call for the international authority as this represents a risk for global public health. The lack of antiviral drugs and effective antibiotics on the market triggers the need to search for safe therapeutics from medicinal plants to fight viral and microbial infections. In the present study, we investigated whether a mangrove plant, Bruguiera gymnorhiza (L.) Lam. (B. gymnorhiza) collected in Mauritius, possesses antimicrobial and antibiotic potentiating abilities and exerts anti-ZIKV activity at non-cytotoxic doses. Microorganisms Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Klebsiella pneumoniae ATCC 70603, methicillin-resistant Staphylococcus aureus ATCC 43300 (MRSA), Salmonella enteritidis ATCC 13076, Sarcina lutea ATCC 9341, Proteus mirabilis ATCC 25933, Bacillus cereus ATCC 11778 and Candida albicans ATCC 26555 were used to evaluate the antimicrobial properties. Ciprofloxacin, chloramphenicol and streptomycin antibiotics were used for assessing antibiotic potentiating activity. ZIKV^MC-MR766NIID (ZIKV^GFP) was used for assessing anti-ZIKV activity. In silico docking (Autodock 4) and ADME (SwissADME) analyses were performed on collected data. Antimicrobial results revealed that Bruguiera twig ethyl acetate (BTE) was the most potent extract inhibiting the growth of all nine microbes tested, with minimum inhibitory concentrations ranging from 0.19–0.39 mg/mL. BTE showed partial synergy effects against MRSA and Pseudomonas aeruginosa when applied in combination with streptomycin and ciprofloxacin, respectively. By using a recombinant ZIKV-expressing reporter GFP protein, we identified both Bruguiera root aqueous and Bruguiera fruit aqueous extracts as potent inhibitors of ZIKV infection in human epithelial A549 cells. The mechanisms by which such extracts prevented ZIKV infection are linked to the inability of the virus to bind to the host cell surface. In silico docking showed that ZIKV E protein, which is involved in cell receptor binding, could be a target for cryptochlorogenic acid, a chemical compound identified in B. gymnorhiza. From ADME results, cryptochlorogenic acid is predicted to be not orally bioavailable because it is too polar. Scientific data collected in this present work can open a new avenue for the development of potential inhibitors from B. gymnorhiza to fight ZIKV and microbial infections in the future.     

In silico modeling and structural analysis of asparaginyl endopeptidase of schistosoma mansoni (Sm32): Immunological and drug target implications

Asparaginyl endopeptidase (AE) of Schistosoma mansoni (Sm32), also known as legumain, is a cysteine protease indirectly involved in the digestion of hemoglobin of Schistosoma sp. in the gastrodermis, being a vaccine candidate against this trematode and a potential drug target. This study presents a model for the three-dimensional structure of Sm32 determined by means of homology modeling and a molecular dynamics simulation with explicit solvent refinement. The structure proved to be consistent with other AEs of known crystal structures described in their proenzyme form, revealing a catalytic domain that has a caspase-like overall structure and a C-terminal prodomain that adopts a death-domain-like architecture. We identified amino acid mutations in the βIV strand, differences in the active site and in the surface electrostatic potentials between Sm32 and its homologous proteins of mouse and human. Additionally, amino acid changes in the activation peptide (AP) of the S. mansoni protein were determined. Our results strongly suggest that Sm32 can be exploited as a potential target for drug design and for the development of biomarkers used in diagnosis and in novel vaccines for the control of parasitic infection, opening the perspective of medicinal chemistry developments.     

Searching Anti-Zika Virus Activity in 1H-1,2,3-Triazole Based Compounds

Zika virus (ZIKV) is a mosquito-borne virus belonging to the Flaviviridae family and is responsible for an exanthematous disease and severe neurological manifestations, such as microcephaly and Guillain-Barré syndrome. ZIKV has a single strand positive-sense RNA genome that is translated into structural and non-structural (NS) proteins. Although it has become endemic in most parts of the tropical world, Zika still does not have a specific treatment. Thus, in this work we evaluate the cytotoxicity and antiviral activities of 14 hybrid compounds formed by 1H-1,2,3-triazole, naphthoquinone and phthalimide groups. Most compounds showed low cytotoxicity to epithelial cells, specially the 3b compound. After screening with all compounds, 4b was the most active against ZIKV in the post-infection test, obtaining a 50% inhibition concentration (IC₅₀) of 146.0 µM and SI of 2.3. There were no significant results for the pre-treatment test. According to the molecular docking compound, 4b was suggested with significant binding affinity for the NS5 RdRp protein target, which was further corroborated by molecular dynamic simulation studies.     

Molecular docking studies of selected tricyclic and quinone derivatives on trypanothione reductase of Leishmania infantum

Visceral leishmaniasis, most lethal form of Leishmaniasis, is caused by Leishmania infantum in the Old world. Current therapeutics for the disease is associated with a risk of high toxicity and development of drug resistant strains. Thiol‐redox metabolism involving trypanothione and trypanothione reductase, key for survival of Leishmania, is a validated target for rational drug design. Recently published structure of trypanothione reductase (TryR) from L. infantum, in oxidized and reduced form along with Sb(III), provides vital clues on active site of the enzyme. In continuation with our attempts to identify potent inhibitors of TryR, we have modeled binding modes of selected tricyclic compounds and quinone derivatives, using AutoDock4. Here, we report a unique binding mode for quinone derivatives and 9‐aminoacridine derivatives, at the FAD binding domain. A conserved hydrogen bonding pattern was observed in all these compounds with residues Thr335, Lys60, His461. With the fact that these residues aid in the orientation of FAD towards the active site forming the core of the FAD binding domain, designing selective and potent compounds that could replace FAD in vivo during the synthesis of Trypanothione reductase can be deployed as an effective strategy in designing new drugs towards Leishmaniasis. We also report the binding of Phenothiazine and 9‐aminoacridine derivatives at the Z site of the protein. The biological significance and possible mode of inhibition by quinone derivatives, which binds to FAD binding domain, along with other compounds are discussed. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Identification of Putative Vaccine and Drug Targets against the Methicillin-Resistant Staphylococcus aureus by Reverse Vaccinology and Subtractive Genomics Approaches

Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen and responsible for causing life-threatening infections. The emergence of hypervirulent and multidrug-resistant (MDR) S. aureus strains led to challenging issues in antibiotic therapy. Consequently, the morbidity and mortality rates caused by S. aureus infections have a substantial impact on health concerns. The current worldwide prevalence of MRSA infections highlights the need for long-lasting preventive measures and strategies. Unfortunately, effective measures are limited. In this study, we focus on the identification of vaccine candidates and drug target proteins against the 16 strains of MRSA using reverse vaccinology and subtractive genomics approaches. Using the reverse vaccinology approach, 4 putative antigenic proteins were identified; among these, PrsA and EssA proteins were found to be more promising vaccine candidates. We applied a molecular docking approach of selected 8 drug target proteins with the drug-like molecules, revealing that the ZINC4235426 as potential drug molecule with favorable interactions with the target active site residues of 5 drug target proteins viz., biotin protein ligase, HPr kinase/phosphorylase, thymidylate kinase, UDP-N-acetylmuramoyl-L-alanyl-D-glutamate-L-lysine ligase, and pantothenate synthetase. Thus, the identified proteins can be used for further rational drug or vaccine design to identify novel therapeutic agents for the treatment of multidrug-resistant staphylococcal infection.     

In Vitro and In Silico Anti-Arboviral Activities of Dihalogenated Phenolic Derivates of L-Tyrosine

Despite the serious public health problem represented by the diseases caused by dengue (DENV), Zika (ZIKV) and chikungunya (CHIKV) viruses, there are still no specific licensed antivirals available for their treatment. Here, we examined the potential anti-arbovirus activity of ten di-halogenated compounds derived from L-tyrosine with modifications in amine and carboxyl groups. The activity of compounds on VERO cell line infection and the possible mechanism of action of the most promising compounds were evaluated. Finally, molecular docking between the compounds and viral and cellular proteins was evaluated in silico with Autodock Vina^®, and the molecular dynamic with Gromacs^®. Only two compounds (TDC-2M-ME and TDB-2M-ME) inhibited both ZIKV and CHIKV. Within the possible mechanism, in CHIKV, the two compounds decreased the number of genome copies and in the pre-treatment strategy the infectious viral particles. In the ZIKV model, only TDB-2M-ME inhibited the viral protein and demonstrate a virucidal effect. Moreover, in the U937 cell line infected with CHIKV, both compounds inhibited the viral protein and TDB-2M-ME inhibited the viral genome too. Finally, the in silico results showed a favorable binding energy between the compounds and the helicases of both viral models, the NSP3 of CHIKV and cellular proteins DDC and β2 adrenoreceptor.     

Design,synthesis and characterization of a series of 6-substituted-4-hydroxy-1-(2-substitutedthiazol-4-yl)quinolin-2(1H)-one derivatives and evaluation of their in vitro anticancer and antibacterial activity

The current research work deals with the design, synthesis and characterization of a series of 6-substituted-4-hydroxy-1-(2-substitutedthiazol-4-yl)quinolin-2(1H)-one derivatives [III(a-d)(1–3)] and evaluation of their in-vitro anticancer activity against MDA-MB (Breast cancer) and A549 (Lung cancer) cell lines based upon MTT assay and in-vitro antibacterial by the measurement of zone of inhibition and determining the Minimum Inhibitory Concentration (MIC). All the synthesized compounds were characterized by UV, IR, ¹H NMR and ¹³C NMR spectral data.Molecular docking studies of the title compounds were carried out using Molegro Virtual Docker (MVD-2013, 6.0) software. The synthesized compounds exhibited well conserved hydrogen bond interactions with one or more amino acid residues in the active pocket of EGFRK tyrosine kinase domain (PDB ID: 1m17) for docking study on anticancer activity and S. aureus DNA Gyrase domain complexed with a ciprofloxacin inhibitor (PDB ID: 2XCT) for antibacterial docking study. All synthesized derivatives were potent against A549 (Lung cancer) cell line as compared to MDA-MB (Breast cancer) cell line. Compound 2-(4-(4-hydroxy-6-methyl-2-oxoquinolin-1(2H)-yl)thiazol-2-yl)hydrazin-1-ium iodide (IIId-2) was found to be the most cytotoxic as compared to the other synthesized derivatives, with IC₅₀ values of 346.12 μg/mL against A549 (Lung cancer) cell line, however all synthesized derivatives were found to be a poor antibacterial agent when compared with standard ciprofloxacin.Thus, the synthesized derivatives possessed a potential to bind with some of the residues of the active site and can be further developed into potential pharmacological agents.     

Synthesis and crystal structure of a chiral lactam and three amino alcohols as potential protein tyrosine phosphates 1B inhibitors

Chiral lactam 2 and three chiral β-amino alcohols 3–5 have been synthesized and characterized by spectroscopic techniques. Regioselective ring opening reaction of chiral styrene oxide by an amine nucleophile was confirmed by X-ray diffraction data. Ligand 2–4 crystallizes in the tetragonal, orthorhombic and tetragonal crystal lattice system respectively. Ligands 2–6 have been used as potential inhibitors for protein tyrosine phosphatase 1B enzyme (PTP1B). The potential inhibitor effect of these molecules to the target protein was investigated by Dock and molecular dynamics calculations. Dock score analysis and Lipinski parameters suggested that ligands 1, 2, 4–6 are potential inhibitors towards PTP1B, thus indicating that the residues Arg24, Arg254 and Met258, Asp29 in the second active site of PTP1B are essential for the high selectivity of inhibitors. The results indicate that the polar hydrogen bonding interacts with Asp29, Gln102, and the amino acid residues of PTP1B are responsible for governing inhibitory potency of ligands 1–6.     

Methylxanthine drugs are chitinase inhibitors: investigation of inhibition and binding modes

Family 18 chitinases play key roles in a range of pathogenic organisms and are overexpressed in the asthmatic lung. By screening a library of marketed drug molecules, we have identified methylxanthine derivatives as possible inhibitor leads. These derivatives, theophylline, caffeine, and pentoxifylline, are used therapeutically as antiinflammatory agents, with pleiotropic mechanisms of action. Here it is shown that they are also competitive inhibitors against a fungal family 18 chitinase, with pentoxifylline being the most potent (K(i) of 37 microM). Crystallographic analysis of chitinase-inhibitor complexes revealed specific interactions with the active site, mimicking the reaction intermediate analog, allosamidin. Mutagenesis identified the key active site residues, conserved in mammalian chitinases, which contribute to inhibitor affinity. Enzyme assays also revealed that these methylxanthines are active against human chitinases.