{"id":16987,"date":"2023-10-04T14:49:19","date_gmt":"2023-10-04T14:49:19","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/blog\/stuck-on-you-discovering-covalent-therapeutics-with-biophysics\/"},"modified":"2023-10-04T14:49:19","modified_gmt":"2023-10-04T14:49:19","slug":"stuck-on-you-discovering-covalent-therapeutics-with-biophysics","status":"publish","type":"blog","link":"https:\/\/www.sygnaturediscovery.com\/fr\/blog\/stuck-on-you-discovering-covalent-therapeutics-with-biophysics\/","title":{"rendered":"Stuck on You: Discovering Covalent Therapeutics with Biophysics"},"content":{"rendered":"<p><span data-contrast=\"auto\">Covalent therapeutics are drug compounds that establish robust and often irreversible connections with their targets, allowing them to remain bound for extended periods compared to conventional non-covalent therapeutics. <\/span><\/p>\n<p><span data-contrast=\"auto\">This potentially has important advantages when developing new treatments. Key to this is the ability to produce an effect at a lower dose, which can be taken less often. Reduced dosing can decrease side effects and make new medicines more economical and easier to take.<\/span><span data-ccp-props='{\"201341983\":0,\"335551550\":6,\"335551620\":6,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">Many drugs on the market have a <a href=\"https:\/\/doi.org\/10.1038\/s41573-022-00542-z\">covalent mode of action<\/a><\/span><span data-contrast=\"auto\">. Interestingly, many of these were initially found to function covalently long after their development and administration to patients, with Aspirin being a well-known example. But what makes the targeted discovery of new covalent therapeutics so challenging, despite there being many available already?\u00a0<\/span><\/p>\n<h2><b><span data-contrast=\"auto\">The challenges of covalent therapeutics<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335551550\":6,\"335551620\":6,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/h2>\n<p>Whilst covalent therapeutics have many advantages, they also have an additional set of risks relative to non-covalent drugs. If a non-covalent drug binds to something other than its target, it will likely do so less well and dissociate before any effects are observed.\u00a0 Covalent molecules are different, once bound they tend to stay bound, meaning that non-target effects are more likely to be serious. It is the goal of any therapeutic pipeline, whether covalent or not, to maximise positive effects and minimise side effects. This can be more of a challenge with a covalent mode of action.<\/p>\n<h2><b><span data-contrast=\"auto\">Filling in the gaps with biophysics<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335551550\":6,\"335551620\":6,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/h2>\n<p>Covalent therapeutics are time-dependent. The formation of a covalent bond is relatively slow, \u00a0which means that the apparent effectiveness of a molecule increases with more time. This is problematic for testing these molecules as this can drastically affect their activity.<\/p>\n<ul>\n<li><span data-contrast=\"auto\">How long does it take to set up the assay?<\/span><\/li>\n<li><span data-contrast=\"auto\"> Can you guarantee that each step is performed for the same second each time? <\/span><\/li>\n<li><span data-contrast=\"auto\">Can the temperature be the same every time too? <\/span><\/li>\n<\/ul>\n<p><span data-contrast=\"auto\">In practice, this is very difficult to do, but this is where SPR comes in.<a href=\"https:\/\/www.sygnaturediscovery.com\/drug-discovery\/bioscience\/biophysical-assays\/surface-plasmon-resonance-spr\/\"> Surface Plasmon Resonance (SPR)<\/a> is a biophysical technique that can observe molecular interactions in real-time. It is also tightly controlled in terms of temperature and contact time, both key parameters in determining the rate of covalent bond formation. This can be used to characterise compounds both from a selectivity perspective (the non-covalent part of an interaction) and reactivity (the covalent part of an interaction). By defining these parameters, we can better guide medicinal chemistry efforts to balance reactivity with selectivity and avoid issues later in the drug discovery process.<\/span><span data-ccp-props='{\"201341983\":0,\"335551550\":6,\"335551620\":6,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">We use this platform in two ways, and it might come as a surprise that one of these approaches is to reduce the covalent part of the interaction so that it effectively disappears. This allows us to identify well-behaved compounds and remove any that have undesirable characteristics, which can sometimes be hidden by covalent activity. This is most important when looking for new hits and starting points for drug discovery, but its significance lessens as molecules become more potent and effective.<\/span><\/p>\n<p><span data-ccp-props='{\"134245418\":true,\"201341983\":0,\"335551550\":6,\"335551620\":6,\"335559739\":160,\"335559740\":259}'> <img decoding=\"async\" class=\"size-medium wp-image-15796 aligncenter\" src=\"https:\/\/www.sygnaturediscovery.com\/wp-content\/uploads\/2025\/11\/Screenshot-2023-09-28-110122.png\" alt=\"\"><\/span><\/p>\n<p><i><span data-contrast=\"none\">Figure <\/span><\/i><i><span data-contrast=\"none\">1<\/span><\/i><i><span data-contrast=\"none\">: Example sensorgrams and binding profiles of desirable (A and B) and undesirable (C and D) binders to a target of interest. The selection of the most promising molecules for advancement relies on assessing both the overall sensorgram shape and the concentration-response curve. Molecules that are saturable and fully dissociating are preferred over those that are not at the hit-finding stage.<\/span><\/i><span data-ccp-props='{\"201341983\":0,\"335551550\":6,\"335551620\":6,\"335559739\":200,\"335559740\":240}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">The second way of using this platform is to fully characterise a covalent binding interaction. This includes examining the initial non-covalent recognition of the binding site, followed by the formation of the covalent bond between the two molecules. This allows us to assess the balance of the molecule\u2019s potency, how much is reactive vs. how much is target recognition and selectivity, providing valuable guidance for the effective development of covalent therapeutics.<\/span><\/p>\n<p><span data-contrast=\"auto\">The overall potency of a covalent molecule is defined by two parameters: k<\/span><span data-contrast=\"auto\">inact<\/span><span data-contrast=\"auto\"> (the rate of covalent bond formation) and K<\/span><span data-contrast=\"auto\">I<\/span><span data-contrast=\"auto\"> (the strength of the non-covalent interaction. We can determine the values of these using the \u201ctwo-state\u201d fitting model, common to many SPR analysis platforms. This model aligns directly with the well-established parameters that have been determined for <a href=\"https:\/\/doi.org\/10.1177\/1087057116671509\">covalent binding<\/a><\/span><span data-contrast=\"auto\">. By using SPR to directly observe these constants, we can provide full characterisation in a relatively high-throughput format compared to other techniques. This technique is universally applicable to all target classes and does not rely on any inherent activity of the target in question.<\/span><\/p>\n<p><img decoding=\"async\" class=\"size-medium wp-image-15797 aligncenter\" src=\"https:\/\/www.sygnaturediscovery.com\/wp-content\/uploads\/2025\/11\/Screenshot-2023-09-28-130223.png\" alt=\"\"><\/p>\n<p><i><span data-contrast=\"none\">Figure <\/span><\/i><i><span data-contrast=\"none\">2<\/span><\/i><i><span data-contrast=\"none\">: The two-state kinetic model aligns with the key parameters of covalent binding. Key to covalent interactions are the parameters k<\/span><\/i><i><span data-contrast=\"none\">inact<\/span><\/i><i><span data-contrast=\"none\"> and K<\/span><\/i><i><span data-contrast=\"none\">I<\/span><\/i><i><span data-contrast=\"none\">. k<\/span><\/i><i><span data-contrast=\"none\">inact<\/span><\/i><i><span data-contrast=\"none\"> is the rate of covalent bond formation and is primarily dictated by k<\/span><\/i><i><span data-contrast=\"none\">2<\/span><\/i><i><span data-contrast=\"none\"> (as k<\/span><\/i><i><span data-contrast=\"none\">-2<\/span><\/i><i><span data-contrast=\"none\"> will be negligible in most cases). K<\/span><\/i><i><span data-contrast=\"none\">I<\/span><\/i><i><span data-contrast=\"none\"> is the non-covalent interaction and is quantified by k<\/span><\/i><i><span data-contrast=\"none\">1<\/span><\/i><i><span data-contrast=\"none\"> and k<\/span><\/i><i><span data-contrast=\"none\">-1<\/span><\/i><i><span data-contrast=\"none\">.<\/span><\/i> <i><span data-contrast=\"none\">The application of SPR data to the covalent inhibitor model allows for effective analysis of covalent binders. In most cases, it is assumed that kd2 = 0, but this can be adjusted for reversible covalent interactions. By using the two-state kinetic model for analysis, <\/span><\/i><i><span data-contrast=\"none\">we can correlate the SPR kinetic output to the traditional covalent kinetic parameters.<\/span><\/i><span data-ccp-props='{\"201341983\":0,\"335551550\":6,\"335551620\":6,\"335559739\":200,\"335559740\":240}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">However, this method comes with its challenges. The nature of covalent molecules means that they inactivate the captured protein surfaces, used in SPR, and potentially block other binders. To maintain throughput and efficiency, the use of regenerable and re-capturable surfaces is crucial <\/span><span data-contrast=\"auto\">and is something that we actively employ in our assays.<\/span><span data-ccp-props='{\"201341983\":0,\"335551550\":6,\"335551620\":6,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-15869 alignleft\" src=\"https:\/\/www.sygnaturediscovery.com\/wp-content\/uploads\/2025\/11\/Lead_Optimisation_Delivering_Molecules_Fit_For_Preclinical_Development_Tilt_Crop.png\" alt=\"\" width=\"431\" height=\"335\"><\/p>\n<h2><\/h2>\n<h2><\/h2>\n<h2 style=\"text-align: left;\"><a href=\"https:\/\/info.sygnaturediscovery.com\/successful-invitro-screening-strategies\"><span style=\"color: #f69a32;\"><span class=\"ui-provider ed bmv bmw bmx bmy bmz bna bnb bnc bnd bne bnf bng bnh bni bnj bnk bnl bnm bnn bno bnp bnq bnr bns bnt bnu bnv bnw bnx bny bnz boa bob boc\" dir=\"ltr\">Download your free eBook: Successful In Vitro Strategies for Drug Discovery<\/span><\/span><\/a><\/h2>\n<p><span style=\"font-size: 10pt;\"><em>Learn more about optimal cascade design, hit-to-lead phase insights and lead optimization strategies<\/em><\/span><\/p>\n<h2><\/h2>\n<h2><\/h2>\n<p>\u00a0<\/p>\n<p>\u00a0<\/p>\n<p>\u00a0<\/p>\n<h2>Supporting Drug Discovery Pipelines<\/h2>\n<p><span data-contrast=\"auto\">A targeted approach to covalent drug discovery often starts with a covalent fragment screen. These are primarily performed using in-tact Mass Spectrometry (MS) as the preferred approach, due to the high-throughput assessment of covalent bond formation as an addition of mass to the target molecule. These reactive fragments are very small and efficient molecules that can be precursors to drug-like molecules, although they can be more challenging to develop. Most drug discovery using fragments requires structural data to enable the development of the molecules with information on how they bind to their target. This can be more difficult with covalent molecules compared to non-covalent molecules,\u00a0<\/span><span data-contrast=\"auto\">but it falls into the range of skills and technologies available at Sygnature.<\/span><span data-ccp-props='{\"201341983\":0,\"335551550\":6,\"335551620\":6,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">Sygnature\u2019s well-established biophysical platform for covalent drug discovery plays a crucial role, especially in the initial hit-finding stage, where validating high-quality hits prepares us for success in a drug discovery campaign. We can apply the platform throughout the life of a project, whether generating data for SAR activities, informing choices between therapeutic series or covalent warhead classes, or generating accurate characterisation data for therapeutic candidates. Our biophysical platform and expertise enable us to actively support covalent drug discovery pipelines with key data that can otherwise be difficult to produce.<\/span><span data-ccp-props='{\"201341983\":0,\"335551550\":6,\"335551620\":6,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p>\u00a0<\/p>\n<h2><strong>About the author<\/strong><\/h2>\n<p>Dr Philip Addis is a highly experienced biophysicist and leads the biophysics group at Sygnature Discovery. Philip has over 10 years of biophysics experience in biotech and CROs, and has supported drug discovery projects for small, medium, and large molecules across a wide range of therapeutic targets.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Dive into the world of covalent therapeutics and their promising benefits in drug development. Discover how biophysics helps us unravel their complexities and optimize their effectiveness in innovative treatments.<\/p>\n","protected":false},"featured_media":16988,"template":"","category":[790,819,1262,850],"class_list":["post-16987","blog","type-blog","status-publish","has-post-thumbnail","hentry","category-bioscience","category-decouverte-integree-de-medicaments","category-essais-biophysiques","category-optimisation-des-leads"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.5 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Stuck on You: Discovering Covalent Therapeutics with Biophysics - Sygnature<\/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:\/\/www.sygnaturediscovery.com\/fr\/blog\/stuck-on-you-discovering-covalent-therapeutics-with-biophysics\/\" \/>\n<meta property=\"og:locale\" content=\"fr_CA\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Stuck on You: Discovering Covalent Therapeutics with Biophysics - Sygnature\" \/>\n<meta property=\"og:description\" content=\"Dive into the world of covalent therapeutics and their promising benefits in drug development. 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