{"id":4745,"date":"2026-03-26T10:13:39","date_gmt":"2026-03-26T10:13:39","guid":{"rendered":"https:\/\/zobio.com\/online\/?p=4745"},"modified":"2026-03-26T13:38:54","modified_gmt":"2026-03-26T13:38:54","slug":"how-screening-covalent-libraries-lands-hits-where-others-fail-2","status":"publish","type":"post","link":"https:\/\/zobio.com\/online\/blog\/how-screening-covalent-libraries-lands-hits-where-others-fail-2\/","title":{"rendered":"How Screening Covalent Libraries Lands Hits Where Others Fail?"},"content":{"rendered":"

How Screening Covalent Libraries Lands Hits Where Others Fail?<\/h2>\n
\n\t

As part of our mission to tackle some of the toughest targets in drug discovery, we\u2019ve recently expanded our early discovery capabilities to include covalent compound library screening. Our early discovery site in Leiden is already well-known for its success in first-in-class and hard-to-drug targets, and this addition reflects a growing shift in the field: covalent approaches are no longer a last resort, they are becoming a smart, mechanism-led starting point for small molecule discovery.<\/span>\u00a0<\/span><\/p>\n

To understand what makes covalent screening so powerful (and what it takes to get it right) we spoke with screening expert and Leiden leader Gregg Siegal. In this Q&A, Gregg shares his perspective on why covalent drugs are in the spotlight and what it takes to perform meaningful hit discovery. We also dig into how to build assays that can unpick the data generated by these high-potential, high-complexity compounds, and why selectivity, structural insight, and kinetics are critical for turning raw reactivity into real therapeutic potential.<\/span>\u00a0<\/span><\/p>\n

Q: Gregg, why are some biotechs pivoting to covalent compounds, and why now?<\/h3>\n

GS: <\/strong>For a long time, covalent compounds carried this stigma that they were too risky, especially from a tox perspective. People thought they\u2019d react with everything in sight and just blow up in the clinic. But that\u2019s been debunked. We\u2019re well past that.<\/p>\n

You\u2019ve got 128 covalent drugs approved by the FDA as of last year1<\/sup>. The first two KRAS drugs that made it through? Covalent. Nobody seriously argues anymore that covalent equals dangerous. That mindset\u2019s gone. What\u2019s changed is that the benefits are now obvious, and the tools to do it right are finally in place.<\/p>\n

Q: What\u2019s the actual advantage of going covalent?<\/h3>\n

GS: <\/strong>It\u2019s your hook. Covalent compounds give you a chemical handle to grab onto a target, even if you don\u2019t have a defined pocket.<\/p>\n

This matters especially for PPI targets, where the surfaces are often flat, flexible, and dynamic. Sometimes pockets only show up 2\u20133% of the time. With fragments or traditional libraries, that\u2019s a nightmare. But a covalent compound doesn\u2019t need the pocket to stay open, it just needs one shot. One good nucleophile, and you\u2019re in.<\/p>\n

Q: What\u2019s the catch? What makes covalent screening hard to do well?<\/h3>\n

GS: <\/strong>Getting a hit isn\u2019t hard. Getting the right<\/strong> hit is where it gets tricky.<\/p>\n

Covalent libraries are full of reactive compounds. Some will react with any residue they encounter. If you\u2019re not careful, you\u2019ll just denature the protein, or trigger aggregation. So, after the screen, you\u2019ve got a pile of raw hits. Some are good, many are not.<\/p>\n

You need to dissect the mechanisms. Are they binding where you want? Are they clean? We run mass spec to make sure you\u2019re getting one or two adducts per protein, not five. We follow that with crystallography to confirm the binding mode. And then we run kinetic profiling to measure kinact<\/sub> and KI<\/sub>. That\u2019s where the expertise matters.<\/p>\n

Q: How do you set up the screen to make sure it\u2019s biologically relevant?<\/h3>\n

GS: <\/strong>We build an assay that reports directly on the biological activity the client wants to see, which these days, is often disruption of a protein\u2013protein interaction. In a recent study, for example, we used a fluorescence polarization assay that showed whether our transcriptional regulator was bound or free.<\/p>\n

We screened 11,000 compounds and looked for a reduction in binding. That tells us a compound blocks binding of the co-transcriptional regulator and not just that it\u2019s reactive. From there, we triage. And that\u2019s where the power of structure comes in. You want to go from raw hits to validated starting points, and you want to do it quickly. We had structures of 7 different hits in a month.<\/p>\n

Q: Who should be looking at covalent screening?<\/h3>\n

GS:\u00a0<\/strong>Anyone working on \u201cunligandable\u201d targets. If we\u2019re honest, that\u2019s a rapidly growing portion of drug developers because the targets we, as an industry, are working with are becoming more and more challenging. Oncology, transcription factors, scaffolding proteins, immune signaling, molecular glues; this is where traditional small molecule approaches might struggle unless you innovate.<\/p>\n

If you\u2019re working with difficult targets, stalled programs, or exploring molecular glues, covalent could be a really smart move. Especially if you\u2019re short on time and need a progressable, structurally enabled hit to start a campaign.<\/p>\n

Q: How can researchers learn more about initiating covalent screening?<\/h3>\n

GS: <\/strong>It sounds clich\u00e9d, but the most straightforward thing to do is send us a message and talk to us. This is what we do, this is what we\u2019re passionate about. We\u2019ll sit down with you and listen. We\u2019ll ask questions and work to understand what you need and what you\u2019re aiming to do. Then our highly experienced early discovery team will work out how we can best help you get to where you need to go. Once you have all the information and a plan, it\u2019s over to you to make a decision on whether to move forward.<\/p>\n

You can explore covalent library screening at the Oncodesign-ZoBio Group by downloading our guide.\u00a0Alternatively, get in touch<\/a> with us for an informal conversation about whether covalent screening might be a viable approach for your tough target.<\/span><\/p>\n

Download Covalent Screening Guide<\/a><\/p>\n

 <\/p>\n

\"\"Dr. Gregg Siegal<\/strong> obtained his Ph.D. in biochemistry at the University of Rochester in the USA. During subsequent post-doctoral research with Professor Kurt W\u00fcthrich at the ETH in Switzerland and Professor Paul Driscoll at the Ludwig Institute of Cancer Research in the UK, Dr. Siegal developed expertise in protein NMR and its applications in modern drug discovery. He moved to Leiden University in 1997 where he received a Dutch Royal Society Fellowship to form his own research group. During this period, he developed the Target-immobilized NMR (TINS) ligand screening technology which became the basis of ZoBio, spun out in 2004 and specializing in complex small molecule early discovery research and hit identification.<\/em><\/p>\n

References<\/strong><\/p>\n

    \n
  1. \u200bDalton, S. E., Pietro, O. D. & Hennessy, E. A Medicinal Chemistry Perspective on FDA-Approved Small Molecule Drugs with a Covalent Mechanism of Action. J. Med. Chem.\u00a068<\/strong>, 2307\u20132313 (2025).<\/li>\n<\/ol>\n

     <\/p>\n<\/div>\n<\/div><\/div><\/div><\/div><\/div><\/div><\/div>","protected":false},"excerpt":{"rendered":"

    As part of our mission to tackle some of the toughest targets in drug discovery, we\u2019ve recently expanded our early discovery capabilities to include covalent compound library screening. Our early discovery site in Leiden is already well-known for its success in first-in-class and hard-to-drug targets, and this addition reflects a growing shift in the field: covalent approaches are no longer a last resort, they are becoming a smart, mechanism-led starting point for small molecule discovery.\u00a0To understand what makes covalent screening so powerful…<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"gpsa_enabled":false,"gpsa_required_form_ids":[],"gpsa_require_unique_form_submission":false,"gpsa_access_behavior":"show_message","gpsa_form_redirect_path":"","gpsa_requires_access_message":"Access to this content requires submission of a form.","gpsa_access":{"type":"session","duration":{"value":30,"unit":"days"}},"gpsa_content_loading_message":"Please wait while we process your submission.","footnotes":""},"categories":[13],"tags":[],"class_list":["post-4745","post","type-post","status-publish","format-standard","hentry","category-blog"],"yoast_head":"\nHow Screening Covalent Libraries Lands Hits Where Others Fail? - ZoBio - Drug Discovery Technology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/zobio.com\/online\/blog\/how-screening-covalent-libraries-lands-hits-where-others-fail-2\/\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"How Screening Covalent Libraries Lands Hits Where Others Fail? - ZoBio - Drug Discovery Technology\" \/>\n<meta property=\"og:description\" content=\"As part of our mission to tackle some of the toughest targets in drug discovery, we\u2019ve recently expanded our early discovery capabilities to include covalent compound library screening. 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