Current Topics in Medicinal Chemistry - Volume 19, Issue 29, 2019

Different kinds of biological activities are defined by complex biochemical interactions, which are termed as a "mathematical function" not only of the molecular structure but also for some additional circumstances, such as physicochemical conditions, interactions via energy and information effects between a substance and organisms, organs, cells. These circumstances lead to the great complexity of prediction for biochemical endpoints, since all "details" of corresponding phenomena are practically unavailable for the accurate registration and analysis. Researchers have not a possibility to carry out and analyse all possible ways of the biochemical interactions, which define toxicological or therapeutically attractive effects via direct experiment. Consequently, a compromise, i.e. the development of predictive models of the above phenomena, becomes necessary. However, the estimation of the predictive potential of these models remains a task that is solved only partially. This mini-review presents a collection of attempts to be used for the above-mentioned task, two special statistical indices are proposed, which may be a measure of the predictive potential of models. These indices are (i) Index of Ideality of Correlation; and (ii) Correlation Contradiction Index.

Background: Designing drug candidates against the urease enzyme, which has been found responsible for many pathological disorders in human beings as well as in animals, was done by insilico means. Methods: Studies were carried out on a designed library of diosmin derivatives with the help of Schrodinger’s maestro package of molecular docking software against a crystallographic complex of plant enzyme Jack bean urease (PDB ID: 3LA4). Best twelve derivatives of diosmin were selected for synthesis by considering their interaction energy along with docking score and were further investigated for antioxidant, urease inhibitory and Anti-H. pylori activity by in- vitro method along with ADMET analysis. Results: In-vitro results of series concluded compounds D2a, D2d and D7 (IC50 12.6 ± 0.002, 14.14 ± 0.001 and 15.64 ± 0.012 μM respectively in urease inhibition and 5.195 ± 0.036, 5.39 ± 0.020 and 5.64± 0.005 μM in antioxidant behavior against DPPH) were found to be significantly potent with excellent docking score -11.721, -10.795, -10.188 and binding energy -62.674, -63.352, -56.267 kJ/ mol as compared to standard drugs thiourea and acetohydroxamic acid (-3.459, -3.049 and -21.156 kJ/mol and - 17.454 kJ/mol) whereas compounds D2b, D5b, D5d and D6 were found moderate in urease inhibitory activity. Conclusion: Selected candidates from the outcome of in-vitro urease inhibitory were further examined for anti- H. pylori activity by a well diffusion method against H. pylori bacterium (DSM 4867). Compound D2a showed good anti-H. Pylori activity with a zone of inhibition 10.00 ± 0.00 mm and MIC value 500μg/mL as compared to standard drug acetohydroxamic acid having a zone of inhibition 9.00 ± 0.50mm and MIC 1000μg/mL. In- silico studies played an important role in designing the potent ligands against urease protein as well as in explaining the binding pattern of designed and synthesized ligand within the active pocket of jack bean urease protein. ADMET studies were also carried out to check the drug similarity of designed compounds by the means of quikprop module of molecular docking software. Hence, the present investigation studies will provide a new vision for the discovery of potent agents against H. pylori and urease associated diseases.

Aim: The aim of this study is to synthesize, characterize and biological evaluation of 3-ethyl 5- methyl2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate derivatives. Background: An efficient synthesis of two series of novel carbamate and sulfonamide derivatives of amlodipine, 3-ethyl 5-methyl 2-(2-aminoethoxy)-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (amlodipine) 1 were chemical synthesized process. Materials & Methods: In this process, various chloroformates 2(a-e) and sulfonyl chlorides 4(a-e) on reaction with 1 in the presence of N,N–dimethylpiperazine as a base in THF at 50-550 oC, the corresponding title compounds 3(a-e) and 5(a-e) in high yields. Furthermore, the compounds 3(a-e) and 5(a-e) were evaluated for antioxidant activity (DPPH method), metal chelating activity, hemolytic activity, antioxidant assay (ABTS method), cytotoxicity, molecular docking and in silico ADMET properties. Results: Results revealed that 5a, 5e, 3d, 3a and 5c exhibited high antioxidant, metal chelating activities, but 5a, 5e and 3d exhibited low activity. The molecular docking studies and ADMET of suggested ligands showed the best binding energies and non-toxic properties. Conclusion: The present in silico and in vitro evaluations suggested that these dihydropyridine derivatives act as potent antioxidants and chelating agents which may be useful in treating metals induced oxidative stress associated diseases.

Background: Glutamate is the principal neurotransmitter in the human brain that exerts its effects through ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The mGluRs are a class of C GPCRs that play a vital role in various neurobiological functions, mGluR1 and mGluR5 are the two receptors distributed throughout the brain involved in cognition, learning, memory, and other important neurological processes. Dysfunction of these receptors can cause neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, X-fragile syndrome, anxiety, depression, etc., hence these receptors are high profile targets for pharmaceutical industries. Objective: The objective of our study is to find the novel dual negative allosteric modulators to regulate both mGluR1 and mGluR5. Methods: In this study, shape screening protocol was used to find the dual negative allosteric modulators for both mGluR1 and mGluR5 followed by ADME prediction, induced-fit docking (IFD) and molecular dynamics simulations. Further, DFT analysis and MESP studies were carried out for the selected compounds. Results: Around 247 compounds were obtained from the eMolecules database and clustered through the CANVAS module and filtered with ADME properties. Furthermore, IFD revealed that the top four compounds (16059796, 25004252, 4667236 and 11670690) having good protein-ligand interactions and binding free energies. The molecular electrostatic potential of the top compounds shows interactions in the amine group and the oxygen atom in the negative potential regions. Finally, molecular dynamics simulations were performed with all the selected as well as the reported compound 29 indicates that the screened hits have better stability of protein ligand complex. Conclusion: Hence, from the results, it is evident that top hits 16059796, 25004252, 4667236 and 11670690 could be a novel and potent dual negative allosteric modulators for mGluR1 and mGluR5.

Objective: In the present study, an attempt has been made for subtractive proteomic analysis approach for novel drug targets in Salmonella enterica subsp. enterica serover Typhi str.CT18 using computational tools. Methods: Paralogous, redundant and less than 100 amino acid protein sequences were removed by using CD-HIT. Further detection of bacterial proteins which are non-homologous to host and are essential for the survival of pathogens by using BLASTp against host proteome and DEG's, respectively. Comparative Metabolic pathways analysis was performed to find unique and common metabolic pathways. The non-redundant, non-homologous and essential proteins were BLAST against approved drug targets for drug targets while Psortb and CELLO were used to predict subcellular localization. Results: There were 4473 protein sequences present in NCBI Database for Salmonella enterica subsp. enterica serover Typhi str. CT18 out of these 327 were essential proteins which were non-homologous to human. Among these essential proteins, 124 proteins were involved in 19 unique metabolic pathways. These proteins were further BLAST against approved drug targets in which 7 cytoplasmic proteins showed druggability and can be used as a therapeutic target. Conclusion: Drug targets identification is the prime step towards drug discovery. We identified 7 cytoplasmic druggable proteins which are essential for the pathogen survival and non-homologous to human proteome. Further in vitro and in vivo validation is needed for the evaluation of these targets to combat against salmonellosis.

Widely advocated for their health benefits worldwide, herbal medicines (HMs) have evolved into a billion dollar generating industry. Much is known regarding their wellness inducing properties, prophylactic and therapeutic benefits for the relief of both minor to chronic ailment conditions given their long-standing use among various cultures worldwide. On the other hand, their equally meaningful chemistry, pharmacokinetic profile in humans, interaction and toxicity profile have been poorly researched and documented. Consequently, this review is an attempt to highlight the health benefits, pharmacokinetics, interaction, and toxicity profile of five globally famous HMs. A systematic literature search was conducted by browsing major scientific databases such as Bentham Science, SciFinder, ScienceDirect, PubMed, Google Scholar and EBSCO to include 196 articles. In general, ginsenosides, glycyrrhizin and curcumin demonstrate low bioavailability when orally administered. Ginkgo biloba L. induces both CYP3A4 and CYP2C9 and alters the AUC and Cmax of conventional medications including midazolam, tolbutamide, lopinavir and nifedipine. Ginsenosides Re stimulates CYP2C9, decreasing the anticoagulant activity of warfarin. Camellia sinensis (L.) Kuntze increases the bioavailability of buspirone and is rich in vitamin K thereby inhibiting the activity of anticoagulant agents. Glycyrrhiza glabra L. displaces serum bound cardiovascular drugs such as diltiazem, nifedipine and verapamil. Herbal medicine can directly affect hepatocytes leading to hepatoxicity based on both intrinsic and extrinsic factors. The potentiation of the activity of concurrently administered conventional agents is potentially lethal especially if the drugs bear dangerous side effects and have a low therapeutic window.