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Two new compounds, lasdiplactone (1) and lasdiploic acid (2) and one known compound 3 were isolated from the chloroform extract of cell free filtrate of the endophytic fungus Lasiosdiplodia pseudotheobromae. The structures of new compounds were determined by interplay of spectral techniques (IR, mass, 1 H NMR, 13 C NMR, DEPT, and 2D NMR). The absolute configuration at C-4 position of 1 was established as S using a process similar to modified Mosher's method. The absolute configuration of 2 was established by comparing its ECD spectrum with the calculated ECD spectra of all possible isomers. In the in vitro XO inhibition assay, the highest inhibition was exhibited by 3 with an IC 50 of 0.38 ± 0.13 μg/ml, followed by 2 with an IC 50 of 0.41 ± 0.1 μg/ml and the least in 1. The oxidized form of 1 also showed high XO inhibition with IC 50 of 0.35 ± 0.13 μg/ml., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Glycogen Synthase Kinase-3 (GSK-3) is a constitutively acting multifunctional serine/threonine kinase, a role of which has been marked in several physiological pathways, making it a potential target for the treatment of many diseases, including Type-II diabetes and Alzheimer's. Design of GSK-3β selective inhibitor was the key challenge which led to the use of rational approaches like structure based methods (molecular docking), and ligand based methods (QSAR, pharmacophore mapping) studies. These methods provide insights into the enzyme-ligand interactions and structure activity relationship of different sets of compounds for the design of promising GSK-3 inhibitors. Molecular dynamic simulation studies have additionally been performed to address key issues like the unique requirement of prime phosphorylation of its substrate at P+4 by GSK-3β. An allosteric site has also been reported, where the binding of the peptide leads to the stabilization of the activation loop, resulting in the enhancement of the catalysis of enzymes. These studies are becoming useful in the design of therapeutically active discriminatory GSK-3 inhibitors. In this article, we present a review of recent efforts and future opportunities for the design of selective GSK-3β inhibitors.

Design and discovery of new potential inhibitors of Plasmodium falciparum dihydrofolate reductase (PfDHFR), equally active against both the wild-type and mutant strains, is urgently needed. In this study, a computer-aided molecular design approach that involved ab initio molecular orbital and density functional theory calculations, along with molecular electrostatic potential analysis, and molecular docking studies was employed to design 15 1H-imidazole-2,4-diamine derivatives as potential inhibitors of PfDHFR enzyme. Visual inspection of the binding modes of the compounds demonstrated that they all interact, via H-bond interactions, with key amino acid residues (Asp54, Ileu/Leu164, Asn/Ser108 and Ile14) similar to those of WR99210 (3) in the active site of the enzymes used in the study. These interactions are known to be essential for enzyme inhibition. These compounds showed better or comparable binding affinities to that of the bound ligand (WR99210). In silico toxicity predictions, carried out using TOPKAT software, also indicated that the compounds are non-toxic.

A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was carried out on cycloguanil derivatives which are reported as growth inhibitors of Plasmodium falciparum clone (T9/94 RC17) which harbors A16V+S108T mutant dihydrofolate reductase (DHFR) enzyme. Comparative of Molecular Field Analysis (CoMFA) and Comparative of Molecular Similarity Indices Analysis (CoMSIA) were carried out to investigate the structural requirements for the activities of these compounds and to derive predictive models that may be used for designing novel PfDHFR enzyme inhibitors. The global minimum energy (within the search space) conformation of the most active compound (38) was obtained by using simulated annealing, and was subsequently used as a template to build the structures of the rest molecules used in the study. The CoMFA model gave statistically significant results with r(cv)(2) and r(ncv)(2) values of 0.654 and 0.951, respectively. The combination of steric, electrostatic and hydrophobic fields resulted in the best CoMSIA model with r(cv)(2) and r(ncv)(2) values of 0.669 and 0.907, respectively. The predictive abilities of the CoMFA and CoMSIA models were also evaluated using test compounds which gave r(pred)(2) values of 0.735 and 0.557, respectively. The results of bootstrapping analyses also confirmed that the generated models are robust and reliable. The models were graphically interpreted using CoMFA and CoMSIA contour plots. The structural regions responsible for the differences in anti-plasmodial activities were analyzed with respect to their electrostatic, steric and hydrophobic nature. The results obtained from this study could be used for rational design of potent inhibitors against A16V+S108T mutant PfDHFR enzyme.

Selective inhibition of inducible nitric oxide synthases (iNOS) has been a challenging problem for researchers pursuing work in finding methods to treat inflammatory disorders, shock, etc. Though many inhibitors have been studied to date, all are associated with selectivity or potency problems. Additionally, most of the reported compounds have several similarities and fewer number of novel structures are being tried. There is an increasing need to design novel molecules for this target. In this work, de novo design using LUDI, combined with docking analysis using FlexX has been employed in an attempt to identify novel scaffolds. Benzene-1,2-diamines were identified which could mimic the interactions of the substrate analogs and other inhibitors. Comparative docking scores in each of the isoforms of nitric oxide synthase were employed to recognize hits for iNOS selectivity.

Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase with varied number of actions in cellular signalling systems making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar affective disorders and Alzheimer's disease. Various efforts have produced many potent small molecule inhibitors of GSK-3, which are being tested for modulation of glycogen metabolism, gene transcription, apoptosis and enhancement of insulin-stimulated glucose transport. Majority of the reported inhibitors show their inhibitory effects towards other phylogenetically related kinases also, like cyclin dependant kinases (CDKs). Thus it is important to develop inhibitors that can inhibit GSK-3 selectively. Rational approaches based on the knowledge of the receptor are best suited to address the selectivity problem. Several crystal structures of GSK-3beta with different ligands are being reported. These are providing the necessary clues regarding the interaction in the ligand binding domain. Several molecular docking efforts are being taken up to identify the clues for enhancing selectivity towards GSK-3. In this review we present current efforts and future opportunities in designing selective GSK-3 inhibitors.

Glycogen synthase kinase-3 (GSK3) is a serine/threonine kinase that has attracted much drug discovery attention in recent years. Structural crystallography of the kinase has produced several high resolution inhibitor-GSK3 complexes and this is offering valuable information about the important pharmacophoric features present in the inhibitor, the protein target and the bioactive conformation. The availability of several GSK3-inhibitor co-crystals was successfully exploited to derive a pharmacophore query which retains the all important inhibitor-GSK3 interaction chemistry. A hypothesis containing three features: two hydrogen bond donors and one hydrogen acceptor was found to explain much of the inhibitor-GSK3 interaction. Subsequently, the query has been submitted to three databases for electronic screening. The hits obtained were docked into glycogen synthase kinase-3beta active site. A total of 21 novel potential leads were proposed after thorough examination by a combination of methods: (i) visual examination of how well they dock into the glycogen synthase kinase-3beta binding site, (ii) detailed analysis of their FlexX, G_Score, PMF_Score, ChemScore and D_Score values, (iii) comparative investigation of the docking scores of the hits with that of the thus far reported inhibitors (iv) determination of the binding mode and examination of how the hits retain interactions with the important amino acid residues of the kinase binding site. The hydrophobic heterocycles identified in this investigation are expected to be important additions to the armamentarium of GSK3 hyperactivity antagonism. Further more, the present work may further our current knowledge of the molecular basis of activation, inhibition and regulation of this pharmaceutically important kinase.

Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is a fascinating enzyme with diverse biological actions in intracellular signaling systems, making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar disorders and Alzheimer's disease. It is important to inhibit GSK-3 selectively and the net effect of the GSK-3 inhibitors thus should be target specific, over other phylogenetically related kinases such as CDK-2. In the present work, we have carried out three-dimensional quantitative structure activity relationship (3D-QSAR) studies on novel class of pyrazolopyrimidine derivatives as GSK-3 inhibitors reported to have improved cellular activity. Docked conformation of the most active molecule in the series, which shows desirable interactions in the receptor, was taken as template for alignment of the molecules. Statistically significant CoMFA and CoMSIA models were generated using 49 molecules in training set. By applying leave-one-out (LOO) cross-validation study, r(cv)2 values of 0.53 and 0.48 for CoMFA and CoMSIA, respectively and non-cross-validated (r(ncv)2) values of 0.98 and 0.92 were obtained for CoMFA and CoMSIA models, respectively. The predictive ability of CoMFA and CoMSIA models was determined using a test set of 12 molecules which gave predictive correlation coefficients (r(pred)2) of 0.47 and 0.48, respectively, indicating good predictive power. Based upon the information derived from CoMFA and CoMSIA contour maps, we have identified some key features that explain the observed variance in the activity and have been used to design new pyrazolopyrimidine derivatives. The designed molecules showed better binding affinity in terms of estimated docking scores with respect to the already reported systems; hence suggesting that newly designed molecules can be more potent and selective towards GSK-3beta inhibition.

Cyclin dependent kinases have emerged as important drug targets with a multitude of therapeutic potentials for their inhibitors. With the purpose of designing new chemical entities with enhanced inhibitory potencies against cyclin dependent kinase 2 (CDK2) and cyclin dependent kinase 1 (CDK1), the 3D-QSAR CoMFA study carried out on oxindole derivatives as inhibitors of these kinases is presented here. The developed model showed a good correlative and predictive ability having a cross validated correlation co-efficient of 0.518 for CDK1 and 0.613 for CDK2. The conventional and predictive correlation coefficients were found to be respectively 0.943 and 0.508 for CDK1 and 0.957 and 0.585 for CDK2. The models could be usefully employed to design dual CDK1 and CDK2 inhibitors and/or to find novel scaffolds through screening of chemical databases.

Protein tyrosine phosphatase-1B (PTP1B) has been demonstrated to play a key role in the negative signalling pathway of insulin. Potent and orally active PTP1B inhibitors are considered to be promising pharmacological agents for the treatment of type-2 diabetes and resistance to weight gain. CoMSIA studies have been preformed on 1,2-naphthoquinone derivatives that are reported to be potential non-peptidic inhibitors of PTP1B. For the selection of dataset to develop the model, the reported molecules were subjected to property filters and segregated into training and test set. As the crystal structure of PTP1B-naphthoquinone derivative is not known, the most active molecule was subjected to simulated annealing dynamics method and the lowest energy conformer was reminimised and considered as the bioactive conformation. Database-inertial alignment was followed for aligning the molecules. Different CoMSIA models were built to get the best related field.

PDHK is a highly specific enzyme, which inhibits PDC thereby reducing the conversion of pyruvate to AcetylCoA leading to increased glucose and lactate level contributing to various pathological disease states. 3D-QSAR CoMFA studies were performed on diverse PDHK inhibitors based on maximum common substructural alignments of different classes of molecules with the selected reference molecule using a divide and conquer strategy. Statistically robust CoMFA model was obtained with a cross-validated correlation coefficient of 0.561 and conventional correlation coefficient of 0.990. Predictive correlation coefficient r2(pred) was found to be 0.875.

Dihydrofolate reductase (DHFR) is a well-known enzyme of the folate metabolic pathway and it is a validated drug target for leishmaniasis. However, only a few leads are reported against Leishmania donovani DHFR (LdDHFR), and thus, there is a need to identify new inhibitors. In this article, pharmacoinformatic tools such as molecular docking, virtual screening, absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, and molecular dynamics (MD) simulations were utilized to identify potential LdDHFR inhibitors. Initially, a natural DHFR substrate (dihydrofolate), a classical DHFR inhibitor (methotrexate), and a potent LdDHFR inhibitor, that is, "5-(3-(octyloxy)benzyl)pyrimidine-2,4-diamine" (LEAD) were docked in the active site of the LdDHFR and MD simulated to understand the binding mode characteristics of the substrates/inhibitors in the LdDHFR. The shape of the LEAD molecule was used as a query for shape-based virtual screening, while the three-dimensional structure of LdDHFR was utilized for docking-based virtual screening. In silico ADMET factors were also considered during virtual screening. These two screening processes yielded 25 suitable hits, which were further validated for their selectivity toward LdDHFR using molecular docking and prime molecular mechanics/generalized born surface area analysis in the human DHFR (HsDHFR). Best six hits, which were selective and energetically favorable for the LdDHFR, were chosen for MD simulations. The MD analysis showed that four of the hits exhibited very good binding affinity for LdDHFR with respect to HsDHFR, and two hits were found to be more selective than the reported potent LdDHFR inhibitor. The present study thus identifies hits that can be further designed and modified as potent LdDHFR inhibitors. [ABSTRACT FROM AUTHOR]

Mechanism-based inhibition (MBI) of cytochrome P450 (CYP) can lead to drug-drug interactions and often to toxicity. Some aliphatic and aromatic amines can undergo biotransformation reactions to form reactive metabolites such as nitrosoalkanes, leading to MBI of CYPs. It has been proposed that the nitrosoalkanes coordinate with the heme iron, forming metabolic-intermediate complex (MIC), resulting in the quasi-irreversible inhibition of CYPs. Limited mechanistic details regarding the formation of reactive nitroso intermediate and its coordination with heme-iron have been reported. A quantum chemical analysis was performed to elucidate potential reaction pathways for the generation of nitroso intermediate and the formation of MIC. Elucidation of the energy profile along the reaction path, identification of three-dimensional structures of reactive intermediates and transition states, as well as charge and spin density analyses, were performed using the density functional B3LYP method. The study was performed using Cpd I [iron (IV-oxo] heme porphine with SH− as the axial ligand) to represent the catalytic domain of CYP, simulating the biotransformation process. Three pathways: (i) N-oxidation followed by proton shuttle, (ii) N-oxidation followed by 1,2-H shift, and (iii) H-abstraction followed by rebound mechanism, were studied. It was observed that the proton shuttle pathway was more favorable over the whole reaction leading to reactive nitroso intermediate. This study revealed that the MIC formation from a primary amine is a favorable exothermic process, involving eight different steps and preferably takes place on the doublet spin surface of Cpd I. The rate-determining step was identified to be the first N-oxidation of primary amine. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In this work, iminothiazolidin-4-one derivatives were explored as selective GSK-3β inhibitors. Molecular docking analysis was carried to design a series of compounds, which were synthesized using substituted thiourea, 2-bromoacetophenones and benzaldehydes. Out of the twenty five compounds synthesized during this work, the in vitro evaluation against GSK-3 led to the identification of nine compounds with activity in lower nano-molar range (2–85 nM). Further, in vitro evaluation against CDK-2 showed five compounds to be selective towards GSK-3. [ABSTRACT FROM AUTHOR]

Abstract: A new class of compounds based on S-benzylated guanylthiourea has been designed as potential PfDHFR inhibitors using computer aided methods (molecular electrostatic potential, molecular docking). Several compounds in this class have been synthesized starting from guanylthiourea and alkyl bromides. In vitro studies showed that two compounds from this class are active with the IC50 value of 100μM and 400nM. [Copyright &y& Elsevier]