AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

AFC analogs as ICMT inhibitors

Isoprenyl cysteine methyltransferase (Icmt) is a membrane bound enzyme that catalyzes the methyl esterification of Ras. This methyl esterification is important in the proper localization of Ras to the plasma membrane, and thus its biological activity. Ras is implicated in ∼30% of human cancer, and in 90% of pancreatic cancer. Therefore small molecules that mislocalize Ras are an attractive therapeutic approach to cancers of this kind. We have performed the first structure activity relationship studies on the isoprenoid chain of N-Acetyl famesyl cysteine (AFC), the minimal synthetic substrate for Icmt. This work led to the synthesis of a small library of prenyl modified analogs and the discovery of the lead inhibitor N-Acetyl (3-isobutenylfarnesyl) Cysteme (Ki = 13.1 μM). To further elaborate the SAR of AFC and develop more potent Icmt inhibitors, modifications to the cysteine amine are of significant interest. Development of a novel solid phase methodology for the synthesis of acyl variants of AFC has been accomplished. The lead amine and isoprenoid modifications can be utilized to design the next generation of Icmt inhibitors. Additionally, the structural content of the prenyl and amine binding regions will be investigated with novel photoaffinity labels, and the binding requirement around the allylic thioether of AFC has been elucidated with an all-carbon bioisostere, which has been synthesized as part of this project. Finally, preliminary work has been completed to utilize protein farnesyltransferase (FTase) as a model system for the evaluation of analogs bearing prenyl moieties in silico through the use of computational docking, pharmacophore construction and quantitative structure activity relationship studies

Evaluation of Models and Data for Assessing Whooping Crane Habitat in the Central Platte River, Nebraska

The primary objectives of this evaluation were to improve the performance of the Whooping Crane Habitat Suitability model (C4R) used by the U.S. Fish and Wildlife Service (Service) for defining the relationship between river discharge and habitat availability, and to assist the Service in implementing improved model(s) with existing hydraulic files. The C4R habitat model is applied at the scale of individual river cross-sections, but the model outputs are scaled-up to larger reaches of the river using a decision support “model” comprised of other data and procedures. Hence, the validity of the habitat model depends at least partially on how its outputs are incorporated into this larger context. For that reason, we also evaluated other procedures including the PHABSIM data files, the FORTRAN computer programs used to implement the model, and other parameters used to simulate the relationship between river flows and the availability of Whooping Crane roosting habitat along more than 100 miles of heterogeneous river channels. An equally important objective of this report was to fully document these related procedures as well as the model and evaluation results so that interested parties could readily understand the technical basis for the Service’s recommendations

Synthesis and Evaluation of Three Structurally Related ¹⁸F‑Labeled Orvinols of Different Intrinsic Activities: 6‑<i>O</i>‑[¹⁸F]Fluoroethyl-diprenorphine ([¹⁸F]FDPN), 6‑<i>O</i>‑[¹⁸F]Fluoroethyl-buprenorphine ([¹⁸F]FBPN), and 6‑<i>O</i>‑[¹⁸F]Fluoroethyl-phenethyl-orvinol ([¹⁸F]FPEO)

We report the synthesis and biological evaluation of a triplet of 6-<i>O</i>-¹⁸F-fluoroethylated derivatives of structurally related orvinols that span across the full range of intrinsic activities, the antagonist diprenorphine, the partial agonist buprenorphine, and the full agonist phenethyl-orvinol. [¹⁸F]­fluoroethyl-diprenorphine, [¹⁸F]­fluoroethyl-buprenorphine, and [¹⁸F]­fluoroethyl-phenethyl-orvinol were prepared in high yields and quality from their 6-<i>O</i>-desmethyl-precursors. The results indicate suitable properties of the three 6-<i>O</i>-¹⁸F-fluoroethylated derivatives as functional analogues to the native carbon-11 labeled versions with similar pharmacological properties