Current and Historical Drivers of Landscape Genetic Structure Differ in Core and Peripheral Salamander Populations

With predicted decreases in genetic diversity and greater genetic differentiation at range peripheries relative to their cores, it can be difficult to distinguish between the roles of current disturbance versus historic processes in shaping contemporary genetic patterns. To address this problem, we test for differences in historic demography and landscape genetic structure of coastal giant salamanders (Dicamptodon tenebrosus) in two core regions (Washington State, United States) versus the species' northern peripheral region (British Columbia, Canada) where the species is listed as threatened. Coalescent-based demographic simulations were consistent with a pattern of post-glacial range expansion, with both ancestral and current estimates of effective population size being much larger within the core region relative to the periphery. However, contrary to predictions of recent human-induced population decline in the less genetically diverse peripheral region, there was no genetic signature of population size change. Effects of current demographic processes on genetic structure were evident using a resistance-based landscape genetics approach. Among core populations, genetic structure was best explained by length of the growing season and isolation by resistance (i.e. a ‘flat’ landscape), but at the periphery, topography (slope and elevation) had the greatest influence on genetic structure. Although reduced genetic variation at the range periphery of D. tenebrosus appears to be largely the result of biogeographical history rather than recent impacts, our analyses suggest that inherent landscape features act to alter dispersal pathways uniquely in different parts of the species' geographic range, with implications for habitat management

Toward antituberculosis drugs: in silico screening of synthetic compounds against Mycobacterium tuberculosis L,D-transpeptidase 2

Junie B Billones,1,2 Maria Constancia O Carrillo,1 Voltaire G Organo,1 Stephani Joy Y Macalino,1 Jamie Bernadette A Sy,1 Inno A Emnacen,1 Nina Abigail B Clavio,1 Gisela P Concepcion31Office of the Vice President for Academic Affairs – Emerging Interdisciplinary Research Program: “Computer-aided Discovery of Compounds for the treatment of Tuberculosis in the Philippines,” Department of Physical Sciences and Mathematics, College of Arts and Sciences, 2Institute of Pharmaceutical Sciences, National Institutes of Health, University of the Philippines Manila, Manila, 3Marine Science Institute, University of the Philippines Diliman, Diliman, Quezon City, PhilippinesAbstract: Mycobacterium tuberculosis (Mtb) the main causative agent of tuberculosis, is the main reason why this disease continues to be a global public health threat. It is therefore imperative to find a novel antitubercular drug target that is unique to the structural machinery or is essential to the growth and survival of the bacterium. One such target is the enzyme L,D-transpeptidase 2, also known as LdtMt2, a protein primarily responsible for the catalysis of 3→3 cross-linkages that make up the mycolyl–arabinogalactan–peptidoglycan complex of Mtb. In this study, structure-based pharmacophore screening, molecular docking, and in silico toxicity evaluations were employed in screening compounds from a database of synthetic compounds. Out of the 4.5 million database compounds, 18 structures were identified as high-scoring, high-binding hits with very satisfactory absorption, distribution, metabolism, excretion, and toxicity properties. Two out of the 18 compounds were further subjected to in vitro bioactivity assays, with one exhibiting a good inhibitory activity against the Mtb H37Ra strain.Keywords: antituberculosis drug discovery, virtual screening, dockin

In silico discovery and in vitro activity of inhibitors against Mycobacterium tuberculosis 7,8-diaminopelargonic acid synthase (Mtb BioA)

Junie B Billones,1,2 Maria Constancia O Carrillo,1 Voltaire G Organo,1 Jamie Bernadette A Sy,1 Nina Abigail B Clavio,1 Stephani Joy Y Macalino,1 Inno A Emnacen,1 Alexandra P Lee,1 Paul Kenny L Ko,1 Gisela P Concepcion3 1OVPAA-EIDR Program, “Computer-Aided Discovery of Compounds for the Treatment of Tuberculosis in the Philippines”, Department of Physical Sciences and Mathematics, College of Arts and Sciences, University of the Philippines Manila, Manila, Philippines; 2Institute of Pharmaceutical Sciences, National Institutes of Health, University of the Philippines Manila, Manila, Philippines; 3Marine Science Institute, College of Science, University of the Philippines Diliman, Quezon City, Philippines Abstract: Computer-aided drug discovery and development approaches such as virtual screening, molecular docking, and in silico drug property calculations have been utilized in this effort to discover new lead compounds against tuberculosis. The enzyme 7,8-diaminopelargonic acid aminotransferase (BioA) in Mycobacterium tuberculosis (Mtb), primarily involved in the lipid biosynthesis pathway, was chosen as the drug target due to the fact that humans are not capable of synthesizing biotin endogenously. The computational screening of 4.5 million compounds from the Enamine REAL database has ultimately yielded 45 high-scoring, high-affinity compounds with desirable in silico absorption, distribution, metabolism, excretion, and toxicity properties. Seventeen of the 45 compounds were subjected to bioactivity validation using the resazurin microtiter assay. Among the 4 actives, compound 7 ((Z)-N-(2-isopropoxyphenyl)-2-oxo-2-((3-(trifluoromethyl)cyclohexyl)amino)acetimidic acid) displayed inhibitory activity up to 83% at 10 µg/mL concentration against the growth of the Mtb H37Ra strain. Keywords: CADDD, ADMET, TOPKAT, BioA inhibitor, structure-based pharmacophore, pharmacophore, molecular docking, resazurin microtiter assa