“Why Small-Molecule Drug Discovery is Having a Moment.” That’s the headline for a recent Chemical & Engineering News article on how innovative tools and techniques are enabling new uses for small molecules. “Rather than losing their attractiveness in the modern world of biological advances, small molecules are having something of a renaissance,” the article reads. “There’s a buzz and a feeling that medicinal chemists can design solutions for diseases they once would have considered impossible to confront.” The biggest change, experts say, is the possibilities opened up by covalent inhibitors and induced-proximity molecules, molecules that go beyond the lock-and-key approach to targeting unwanted proteins. (Speaking of covalence brings to mind Derek Lowe’s recent blog for Science, titled “More Covalent Compounds Than You Can Imagine”). The Chemical & Engineering News article ends with a quote from Zoë Waller, an Associate Professor in Drug Discovery at University College London, who predicts: “I envision there will be types of drugs that will look weird to us because they don’t look like what we’re expecting. And that’s what we need. . . . There’s so much potential there.” From a software perspective, it is all about handling and analyzing the data patterns, regardless of the therapeutic modality. CDD Vault supports biologics registration and SAR since January 2022, in addition to small molecules and hybrid entities.
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A Cure at Last for Sickle Cell Disease? The New York Times carries an article headlined “Panel Says That Innovative Sickle Cell Cure Is Safe Enough for Patients.” The decision by an advisory committee may lead to FDA approval of the first treatment for humans that uses the CRISPR gene-editing system. Known as exa-cel, the treatment was jointly developed by Vertex Pharmaceuticals of Boston and CRISPR Therapeutics of Switzerland. Sickle cell afflicts more than 100,000 Americans, most of whom have African ancestry. The severity of the disease is illustrated by one example in the article, of an 8-year-old girl who had 22 blood transfusions and had to have her spleen removed before she was 3. “We are finally at a spot where we can envision broadly available cures for sickle cell disease,” said Dr. John Tisdale, Director of the Cellular and Molecular Therapeutics Branch at the National Heart, Lung and Blood Institute and a member of the advisory committee. CRISPR snips a piece of DNA in bone marrow stem cells, freeing a blocked gene to create normally shaped hemoglobin. In clinical trials, patients no longer had the complications of sickle cell disease and no longer needed blood transfusions. While potentially life-changing, the treatment will likely require specialized hospitals, as it involves “Eight weeks of blood transfusions followed by a treatment to release bone marrow stem cells into their bloodstream. The stem cells are then removed and sent to the companies to be treated. Next, patients receive intense chemotherapy to clear their marrows for the treated cells. The treated cells are infused back into the patients, but they have to remain in the hospital for at least a month while the new cells grow and repopulate their marrows”.
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“DeepMind’s Latest AlphaFold Model is More Useful for Drug Discovery.” Google’s DeepMind lab says its newest release of AlphaFold, the successor to AlphaFold 2, can generate predictions for nearly all molecules in the Protein Data Bank, the world’s largest open access database of biological molecules. That’s according to a recent article in TechCrunch which also notes that “The new AlphaFold’s capabilities extend beyond protein prediction. DeepMind claims that the model can also accurately predict the structures of ligands—molecules that bind to ‘receptor’ proteins and cause changes in how cells communicate—as well as nucleic acids (molecules that contain key genetic information) and post-translational modifications (chemical changes that occur after a protein’s created).” The AlphaFold team has released a white paper providing a deeper look.
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Altering the Gut Microbiome to Enhance Cancer Immunotherapy. A team at Harvard Medical School is exploring the mechanisms that gut microbes use to influence how patients respond to immunotherapy. Along the way they found a bacterial species that downregulates the expression of two molecules on immune cells in a mouse cancer model. One of these molecules, the repulsive guidance molecule B (RGMb), had not previously been associated with immunotherapy resistance, so the findings, published in Nature, may open the door to developing new strategies to complement existing treatments, according to a recent article in Drug Discovery News. The discovery provides insight into why in both animal models and clinical settings, individuals who respond favorably to immunotherapy tend to harbor more of specific gut microbes compared to those who do not.
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Barry A. Bunin, PhD, is the Founder & CEO of Collaborative Drug Discovery, which provides a modern approach to drug discovery research informatics trusted globally by thousands of leading researchers. The CDD Vault is a hosted biological and chemical database that securely manages your private and external data.