Structure-based virtual ligand screening is emerging as a key paradigm for early drug discovery owing to the availability of high-resolution target structures and ultra-large libraries of virtual compounds. However, to keep pace with the rapid growth of virtual libraries, such as readily available for synthesis (REAL) combinatorial libraries, new approaches to compound screening are needed. Here we introduce a modular synthon-based approach-V-SYNTHES-to perform hierarchical structure-based screening of a REAL Space library of more than 11 billion compounds. V-SYNTHES first identifies the best scaffold-synthon combinations as seeds suitable for further growth, and then iteratively elaborates these seeds to select complete molecules with the best docking scores. This hierarchical combinatorial approach enables the rapid detection of the best-scoring compounds in the gigascale chemical space while performing docking of only a small fraction (<0.1%) of the library compounds. Chemical synthesis and experimental testing of novel cannabinoid antagonists predicted by V-SYNTHES demonstrated a 33% hit rate, including 14 submicromolar ligands, substantially improving over a standard virtual screening of the Enamine REAL diversity subset, which required approximately 100 times more computational resources. Synthesis of selected analogues of the best hits further improved potencies and affinities (best inhibitory constant (K) = 0.9 nM) and CB/CB selectivity (50-200-fold). V-SYNTHES was also tested on a kinase target, ROCK1, further supporting its use for lead discovery. The approach is easily scalable for the rapid growth of combinatorial libraries and potentially adaptable to any docking algorithm.
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http://dx.doi.org/10.1038/s41586-021-04220-9 | DOI Listing |
J Med Internet Res
December 2024
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
Background: Mobile health (mHealth) interventions have gained popularity in augmenting psychiatric care for adults with psychosis. Interest has grown in leveraging mHealth to empower individuals living with severe mental illness and extend continuity of care beyond the hospital to the community. However, reported outcomes have been mixed, likely attributed in part to the intervention and adopted outcomes, which affected between-study comparisons.
View Article and Find Full Text PDFChemMedChem
December 2024
University of Ljubljana, Faculty of Pharmacy, Askerceva cesta 7, 1000, Ljubljana, SLOVENIA.
Seven different enzymes comprise the galactosyltransferases family, of which β-1,4-galactosyltransferase I (β-1,4-GALT1) is the major contributor to galactosylation activity in cells. Since abnormalities in galactosylation are associated with many pathophysiological conditions, β-1,4-GALT1 is an interesting new target for drug discovery and molecular probe design. There are several known β-1,4-GALT1 inhibitors, but most of them suffer from low cell permeability and thus low in vivo activity.
View Article and Find Full Text PDFJ Biomol Struct Dyn
December 2024
Amity Institute of Biotechnology, Amity University, Kolkata, India.
The first FDA approved, MDR-TB inhibitory drug bedaquiline (BDQ), entraps the c-ring of the proton-translocating F region of enzyme ATP synthase of , thus obstructing successive ATP production. Present-day BDQ-resistance has been associated with cardiotoxicity and mutation(s) in the atpE gene encoding the c subunit of ATP synthase (ATPc) generating five distinct ATPc mutants: Ala63→Pro, Ile66→Met, Asp28→Gly, Asp28→Val and Glu61→Asp. We created three discrete libraries, first by repurposing bedaquiline via scaffold hopping approach, second one having natural plant compounds and the third being experimentally derived analogues of BDQ to identify one drug candidate that can inhibit ATPc activity more efficiently with less toxic properties.
View Article and Find Full Text PDFG protein-coupled receptors (GPCRs) remain a focal point of research due to their critical roles in cell signaling and their prominence as drug targets. However, directly linking drug efficacy to receptor-mediated activation of specific intracellular transducers and the resulting physiological outcomes remains challenging. It is unclear whether the enhanced therapeutic window of certain drugs - defined as the dose range that provides effective therapy with minimal side effects - stems from their low intrinsic efficacy across all signaling pathways or ligand bias, wherein specific transducer subtypes are preferentially activated in a given cellular system compared to a reference ligand.
View Article and Find Full Text PDFJ Chem Inf Model
December 2024
Orion Pharma, Orionintie 1A, 02101 Espoo, Finland.
Given the size of the relevant chemical space for drug discovery, working with fully enumerated compound libraries (especially in three-dimensional (3D)) is unfeasible. Nonenumerated virtual chemical spaces are a practical solution to this issue, where compounds are described as building blocks which are then connected by rules. One concrete example of such is the BioSolveIT chemical spaces file format (.
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