New Developments in Medicinal Chemistry

Volume: 2

Estimating Protein-Ligand Binding Affinity by NMR

Author(s): Susimaire Pedersoli Mantoani, Peterson de Andrade and Carlos Henrique Tomich de Paula da Silva

Pp: 170-191 (22)

DOI: 10.2174/9781608059546114020005

* (Excluding Mailing and Handling)

Abstract

Deep knowledge of how the binding processes occur, such as drugreceptor, signal transduction and cellular recognition, is indispensable for a greater understanding of biological functions. Medicinal chemistry in the path of drug discovery has focused on studies of the molecular interactions which are involved in the development of severe disease state. Thereby, an accurate knowledge about the underlying protein receptor-ligand recognition events at atomic level is fundamental in the process to comprehension, identification and optimization of more potent drug candidates. In this sense, several novel NMR spectroscopic techniques can yield insight into protein-protein interactions in solutions at the molecular level. Resonance signal of the protein or the ligand can be used to identify binding events from a broad range of experiments. For this purpose, changes in NMR spectroscopy parameters such as chemical shifts, relaxation times, diffusion constants, NOEs or exchange of saturation can serve as a measure of binding. In this chapter, the main NMR experimental approaches applied to characterize protein-ligand binding affinity will be discussed. Thus, we hope to provide the reader with a broader and better understanding of how NMR spectroscopy techniques can be applied to a drug discovery process.


Keywords: 13C-labeled protein, 15N-labeled protein, binding affinity, diffusion constant, diffusion ordered spectroscopy (dosy), drug discovery, hsqc (heteronuclear single quantum coherence), intermolecular interaction, nmr screening methods, nuclear magnetic resonance (nmr), nuclear overhauser effects (noe), protein-ligand interaction, relaxation time, std (saturation transfer difference), trosy (transverse relaxation optimized spectroscopy), waterlogsy (water-ligand observed via Gradient Spectroscopy).

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      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 58766425 and j.to_ip >=58766425 )) and ((j.from_date <= 1739847133 and j.to_date >= 1739847133 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6759) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 58766425 and j.to_ip >=58766425 )) and ((j.from_date <= 1739847133 and j.to_date >= 1739847133 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6759) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 58766425 and j.to_ip >=58766425 )) and ((j.from_date <= 1739847133 and j.to_date >= 1739847133 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 6759)
      780μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 1536 and `b`.`banner_from_date` <= 1739847133 and `b`.`banner_to_date` >= 1739847133 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.49msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 1536
      • 3: 1739847133
      • 4: 1739847133
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='3b12d984c370b6a70d51114eff2d3408'
      270μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    16Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        YIYzdYBhB6H6ri9cKiCvDgSwGeRqwSTaYi1Zw8ru
        uc_cart_id
        3b12d984c370b6a70d51114eff2d3408
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/6759" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/6759
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:17 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6IjdGemFTVVBtTTJHZ3lKbkNLWFNVRXc9PSIsInZhbHVlIjoiUFhwaVNiOHZhTlhXQXhSdTlSOWl3YjF6eXFRRGhPNlZlYVlxOUxpdXRuUT0iLCJtYWMiOiI2YzdjZWE5MmQ2MDA0NGRmOGE1NjkyOGI3MjRhNjM3MmFlN2Y1ZTIyMzNkNTk5NzA2ZWRlNGY1YTAyNzRmNDIzIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IjdGemFTVVBtTTJHZ3lKbkNLWFNVRXc9PSIsInZhbHVlIjoiUFhwaVNiOHZhTlhXQXhSdTlSOWl3YjF6eXFRRGhPNlZlYVlxOUxpdXRuUT0iLCJtYWMiOiI2YzdjZWE5MmQ2MDA0" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 18 Feb 2025 02:52:13 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlZLTzRYcExxRm1WOU94RTZXelhxV3c9PSIsInZhbHVlIjoiMXVhb3l1eE9VUHJrZVIwc25Ca3B0VGZNMFNGc0tKNGxxanZQU3pBQ1E3ckQxaXQzZTR2K3ZvSXVYZkh0c2I1U1dpS3N6S1ZFNlN3WERZbk5XYkdZYk5QNGh3RnlmdmcvVHlRS1E0ZDlxUXo1R0dDUnpvMHNDTHl0MWlJK011S2wiLCJtYWMiOiI4NDExYjVhY2MwMTQzM2ZiNzY3MTgyZTY2ZWM0ZjA2YTI3N2ZkMjYxMTM3NjhmNDQxMGVkYzRjM2IyNGQ3YzdlIiwidGFnIjoiIn0%3D; expires=Thu, 20 Feb 2025 14:52:13 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IlZLTzRYcExxRm1WOU94RTZXelhxV3c9PSIsInZhbHVlIjoiMXVhb3l1eE9VUHJrZVIwc25Ca3B0VGZNMFNGc0tKNGxxanZQU3pBQ1E3ckQxaXQzZTR2K3ZvSXVYZkh0c2I1U1dpS3N6S" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImRleVh6K05kMzRtL2hGdGFmNWpQRmc9PSIsInZhbHVlIjoidmoyOG5PNitsR2RYdkoveG9nclJQK0M0M1U0VlJrY0J3UzhiYVNIQ0V3aS9IcVVZR283Uy9sL1ljMUF0YkEvTWQwM2wrVEk3QXRyTHo5UzdmVmpPaGlrRXFReHQwVStRQkFFNmdxR1NKUkVpS1hFRUl0amdxUUVQQ1ZhZUYvSFMiLCJtYWMiOiJjMDFkYWY1N2M5ZGVkOGQ2ODc0ZjJlODZjZjVmNjc3MmYzZTM5NDkxOWRiMjQxNDk4MGY5ZGMxNDczODMzZDE4IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6ImRleVh6K05kMzRtL2hGdGFmNWpQRmc9PSIsInZhbHVlIjoidmoyOG5PNitsR2RYdkoveG9nclJQK0M0M1U0VlJrY0J3UzhiYVNIQ0V3aS9IcVVZR283Uy9sL1l" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlZLTzRYcExxRm1WOU94RTZXelhxV3c9PSIsInZhbHVlIjoiMXVhb3l1eE9VUHJrZVIwc25Ca3B0VGZNMFNGc0tKNGxxanZQU3pBQ1E3ckQxaXQzZTR2K3ZvSXVYZkh0c2I1U1dpS3N6S1ZFNlN3WERZbk5XYkdZYk5QNGh3RnlmdmcvVHlRS1E0ZDlxUXo1R0dDUnpvMHNDTHl0MWlJK011S2wiLCJtYWMiOiI4NDExYjVhY2MwMTQzM2ZiNzY3MTgyZTY2ZWM0ZjA2YTI3N2ZkMjYxMTM3NjhmNDQxMGVkYzRjM2IyNGQ3YzdlIiwidGFnIjoiIn0%3D; expires=Thu, 20-Feb-2025 14:52:13 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IlZLTzRYcExxRm1WOU94RTZXelhxV3c9PSIsInZhbHVlIjoiMXVhb3l1eE9VUHJrZVIwc25Ca3B0VGZNMFNGc0tKNGxxanZQU3pBQ1E3ckQxaXQzZTR2K3ZvSXVYZkh0c2I1U1dpS3N6S" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImRleVh6K05kMzRtL2hGdGFmNWpQRmc9PSIsInZhbHVlIjoidmoyOG5PNitsR2RYdkoveG9nclJQK0M0M1U0VlJrY0J3UzhiYVNIQ0V3aS9IcVVZR283Uy9sL1ljMUF0YkEvTWQwM2wrVEk3QXRyTHo5UzdmVmpPaGlrRXFReHQwVStRQkFFNmdxR1NKUkVpS1hFRUl0amdxUUVQQ1ZhZUYvSFMiLCJtYWMiOiJjMDFkYWY1N2M5ZGVkOGQ2ODc0ZjJlODZjZjVmNjc3MmYzZTM5NDkxOWRiMjQxNDk4MGY5ZGMxNDczODMzZDE4IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6ImRleVh6K05kMzRtL2hGdGFmNWpQRmc9PSIsInZhbHVlIjoidmoyOG5PNitsR2RYdkoveG9nclJQK0M0M1U0VlJrY0J3UzhiYVNIQ0V3aS9IcVVZR283Uy9sL1l" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "YIYzdYBhB6H6ri9cKiCvDgSwGeRqwSTaYi1Zw8ru" "uc_cart_id" => "3b12d984c370b6a70d51114eff2d3408" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/6759" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-18 02:52:13GET/chapter/67591121918