Fragment-based drug discovery (FBDD) can more efficiently scan chemical space to provide novel hits for developing new therapeutics. Protein X-ray crystallography (PX) is the gold standard for experimentally defining exact binding of a ligand to asses direct target engagement. Absence of crystal structures of target-ligand complexes is a significant impediment to medicinal chemistry optimization of hits. Conventional crystallography is inefficient for screening a large fragment or scaffold library due to expense and effort. Complementary biophysics experimental methods like SPR, NMR or TSA are often used to prescreen for ligands that bind, while PX is used in a second step to determine the exact binding of each ligand. With foundational expertise in structural biology, structural genomics and high-throughput (HT) PX, our novel platform, ABS-OneStep, for hit generation in early drug discovery simultaneously combines PX and FBDD.ABS-OneStep for ultra-HT PX-based fragment and scaffold library screening (cryo or room temperature structures) accelerates hit and hit-to-lead generation by directly providing 3D structures of target-bound ligands leading to ∼10x reduction in early drug discovery effort while generating intellectual property by discovering binding sites and protein-ligand interactions. This provides us with an unprecedented experimental route to high quality, high reliability and high value results simultaneously with a high hit rate and multiple hits: identification and assessment of target engagement by ligand binding sites and poses; target ligandability; and differentiation of orthosteric and allosteric sites and binders. Generation of experimentally-validated hits at scale bypasses speculation and guesswork from computational screening of libraries, which desire crystal structures for validation. We also developed a companion module for deep data analytics on protein-ligand interactions from the experimental data and structures, thereby providing even more insight to fill gaps between structural biology and biology/medicinal/computational chemistry in drug discovery to feed into our ML/AI-based methods to advance hits to leads and iterative structure-guided optimization.We will present results on different targets including advancing from hits to functional leads in several weeks and enabling new therapeutics development for traditionally undruggable targets like DNA-binding proteins. These leads can be pursued in parallel for developing both small molecule inhibitors and target ligands in targeted protein degradation.

Hit generation and data in early drug discovery by crystallography-based library screening

作者: Das, Debanu

Fragment-based drug discovery (FBDD) can more efficiently scan chem. space to provide novel hits for developing new therapeutics.Protein X-ray crystallog. (PX) is the gold standard for exptl. defining exact binding of a ligand to asses direct target engagement.Absence of crystal structures of target-ligand complexes is a significant impediment to medicinal chem. optimization of hits.Conventional crystallog. is inefficient for screening a large fragment or scaffold library due to expense and effort.Complementary biophysics exptl. techniques, such as SPR, NMR or TSA are often used to prescreen for ligands that bind, while PX is used in a second step to determine the exact binding of each ligand.With foundational expertise in structural biol., structural genomics and high-throughput (HT) PX, we have developed a novel platform, ABS-OneStep, for hit generation in early drug discovery that simultaneously combines PX and FBDD.ABS-OneStep for ultra-HT PX-based fragment and scaffold library screening (cryo or room temperature structures) accelerates hit and hit-to-lead generation by directly providing 3D structures of target-bound ligands leading to ∼10x reduction in early drug discovery effort while generating intellectual property by discovering binding sites and protein-ligand interactions.This provides us with an unprecedented exptl. route to high quality, high reliability and high value results simultaneously with a high hit rate and multiple hits: identification and assessment of target engagement by ligand binding sites and poses; target ligandability; and differentiation of orthosteric and allosteric sites and binders.Generation of exptl.-validated hits at scale bypasses speculation and guesswork from computational screening of libraries, which desire crystal structures for validation.We also developed a companion module for deep data analytics on protein-ligand interactions from the exptl. data and structures, thereby providing even more insight to fill gaps between structural biol. and biol./medicinal/computational chem. in drug discovery.We will present results on various targets including advancing from hits to functional leads in several weeks and enabling new therapeutics development for traditionally undruggable targets like DNA-binding proteins.These leads can be pursued in parallel for developing both small mol. inhibitors and target ligands in targeted protein degradation

Early drug discovery hit generation by ultrahigh-throughput crystallography-based screening

作者: Das, Debanu

Fragment-based drug discovery (FBDD) is widely used in the pharmaceutical industry to provide novel hits for developing new therapeutics.It allows a more efficient scanning of chem. space with a higher hit rate compared to high-throughput screening, and this has important outcomes in early drug discovery.Protein X-ray crystallog. (PX) is the gold standard for exptl. defining exact binding of a ligand to asses directly target engagement.Absence of crystal structures of target-ligand complexes is a significant impediment to medicinal chem. optimization of hits.Conventional crystallog. is inefficient for screening a large fragment or scaffold library due to expense and effort.Complementary exptl. techniques, such as SPR, NMR or TSA are often used to prescreen for ligands that bind, while crystallog. is used in a second step to determine the exact binding of each ligand.With foundational expertise in structural biol., structural genomics and HT PX, we have developed novel methods for hit generation in early drug discovery.Our platform for ultrahigh-throughput crystallog.-based fragment and scaffold library screening (cryo or room temperature structures) accelerates hit generation and hit-to-lead development by directly providing 3D structures of target-bound ligands, potentially leading to ∼5-7x reduction in early drug discovery effort while generating IP in the form of identifying binding sites and protein-ligand interactions.This provides unprecedented exptl. route to high quality, high reliability and high value results simultaneously: identification and assessment of target engagement by ligand binding sites and poses; target ligandability; and differentiation of orthosteric and allosteric sites and binders.We will present results on various targets; and how it has helped to spur growth of new therapeutics discovery and development, resulting in advancing from hits to functional leads in several weeks.

项与 Accelero Biostructures, Inc. 相关的新闻（医药）

2024-09-04

·PRNewswire

Mid-Atlantic BioTherapeutics Collaborates with Accelero Biostructures to Develop Novel USP30 Inhibitors for Multiple Therapeutic Indications

DOYLESTOWN, Pa., Sept. 4, 2024 /PRNewswire/ -- Mid-Atlantic BioTherapeutics (MABT) and Accelero Biostructures (Accelero) are pleased to announce a research collaboration to identify novel USP30 inhibitors targeting neurological disorders and other important medical indications. Accelero will use its novel and proprietary ABS-OneStepSM platform based on high-throughput protein X-ray crystallography-based fragment screening as the hit generation engine for drug discovery coupled with machine learning/artificial intelligence (ML/AI)-based computational chemistry. MABT will perform all preclinical testing and will also assume advanced development of the resulting compounds. MABT CEO David Horn, M.D. commented that "USP30 is an exciting, emerging target that, once effectively modulated, may have a meaningful clinical impact on several neurological disorders like Alzheimer's and Parkinson's Diseases, as well as a range of other medical targets. We are looking forward to working with the Accelero team to rapidly discover novel compounds using their powerful ABS-OneStep platform." "Our partnership with MABT further validates the promise of our ABS-OneStep platform to discover novel chemical matter that targets promising proteins like USP30," said Debanu Das, Ph.D., Accelero Co-Founder and CEO. "The ABS-OneStep platform has been successfully utilized on multiple diverse protein targets, and we are confident the platform will identify new molecules against USP30." About USP30 USP30 is a deubiquitinating enzyme (DUB) that plays a crucial role in regulating cellular processes, particularly those related to mitochondria. USP30 regulates mitophagy, a process where damaged mitochondria are selectively removed from cells. This process is essential for maintaining cellular health and preventing oxidative stress. Mounting evidence has shown that USP30 may play an important role in various neurological diseases. About MABT Mid-Atlantic BioTherapeutics (MABT) was founded in 2011 with the mission of combating some of the world's worst diseases like rabies encephalitis, Alzheimer's and Parkinson's Disease and other severe neurological disorders. We have received Orphan Drug Designation for our lead rabies program and are developing novel treatments for a range of other neurological disorders. Fundamentally, we are opportunistic in our evaluation of new strategies and approaches that address a significant medical need and commercial market. About Accelero Accelero Biostructures was founded in 2015 to capitalize on over 20 years of structural genomics and structural biology expertise developing and deploying high-throughput protein X-ray crystallography. ABS-ServicesSM provides a unified pipeline of protein X-ray crystallography solutions aimed at the pharmaceutical and biotechnology industries to support structure-based drug discovery and protein engineering. ABS-OneStepSM is the next-generation platform for hit generation in early drug discovery to develop novel therapeutics using a fragment-based drug discovery (FBDD) approach. Fragment library screening with ABS-OneStepSM resolves key bottlenecks in conventional FBDD approaches. ABS-OneStepSM provides an extremely sensitive, efficient, experimental, single-step approach for determining fragment hits and their 3D structures using high-throughput protein X-ray crystallography. Disclaimer Development of the ABS-OneStepSM platform for high-throughput protein X-ray crystallography-based fragment screening has been supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under Award Number R43TR001736, and the National Institute of General Medical Sciences of the NIH under Award Number R44GM132796, to Accelero Biostructures Inc. SOURCE Mid-Atlantic BioTherapeutics, Inc.

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