New perspectives in lead generation II: Evaluating molecular diversity

Use of Direct-Infusion Electrospray Mass Spectrometry To Guide Empirical Development of Improved Conditions for Expression of Secondary Metabolites from Actinomycetes

“…Historically, the secondary metabolite discovery process has been guided by activity-based screening approaches that identify active extracts based on their ability to affect a specific biological assay (4,40). Activity-based screening often results in enrichment of compounds that are already known and is subject to high falsepositive rates due to the complex nature of natural product extracts (27).…”

“…), 2 g of MgSO 4 , 5 g of glucose, and 4 g of maltose. At the mid-log phase, 60 l (ϳ0.4% inoculum) of each vegetative culture was transferred into 12 ml of complex growth medium A, which contained (per liter) 10 g of glucose, 40 g of potato dextrin (Avedex, Keokuk, Iowa), 15 g of cane molasses (Cargill, Minneapolis, Minn.), 10 g of Hy-case amino (Sheffield Products, Norwich, N.Y.), 1 g of MgSO 4 , and 2 g of CaCO 3 ; the final pH was 7.0. Other complex fermentation media used for submerged fermentations included medium B, which contained The fermentation vessel consisted of a rectangular Axid (Eli Lilly and Co., Indianapolis, Ind.)…”

“…Cultures of 44 actinomycetes (Table 1) were started from cryogenic stocks in a vegetative medium that contained (per liter) 30 g of tryptic soy broth (Difco Laboratories, Detroit, Mich.), 3 g of yeast extract (Sigma Chemical Co., St. Louis, Mo. ), 2 g of MgSO 4 , 5 g of glucose, and 4 g of maltose. At the mid-log phase, 60 l (ϳ0.4% inoculum) of each vegetative culture was transferred into 12 ml of complex growth medium A, which contained (per liter) 10 g of glucose, 40 g of potato dextrin (Avedex, Keokuk, Iowa), 15 g of cane molasses (Cargill, Minneapolis, Minn.), 10 g of Hy-case amino (Sheffield Products, Norwich, N.Y.), 1 g of MgSO 4 , and 2 g of CaCO 3 ; the final pH was 7.0.…”

“…In recent years, several factors have increased the difficulty of discovering secondary metabolites with the potential to be drug leads. These factors include the difficulty of managing the compatibility of complex natural extracts with high-throughput and ultra-high-throughput screening methods, the reality that most discoveries are rediscoveries of known compounds, and competition from laboratory-synthesized chemical diversity, the supply of which has been dramatically increased by combinatorial methods (4,14). However, human awareness of microbial biodiversity has expanded tremendously in the past few years, so we now recognize that less than a few percent of the biodiversity on earth have been evaluated in drug-screening programs (37).…”

Predicting Molecular Interactions in silico: I. A Guide to Pharmacophore Identification and its Applications to Drug Design

“…Pharmacophore fingerprints have a wide range of applications. They can be used to measure molecular similarity [69,70], to design libraries, to assess their diversity and to search them for novel active compounds [37,66,[71][72][73][74][75][76][77][78][79][80].…”