Frontiers in Computational Chemistry

Volume: 1

Computational Chemistry Strategies Tackling Function and Inhibition of Pharmaceutically Relevant Targets

Author(s): Michele Cascella, Matteo Dal Peraro and Marco De Vivo

Pp: 290-343 (54)

DOI: 10.2174/9781608058648115010010

* (Excluding Mailing and Handling)

Abstract

Computational methods relying on first principles are fundamental for dissecting basic physicochemical properties of biological systems and unveiling mechanistic details that are often silent to experiments. The tireless improvement of theoretical schemes for molecular modelling and simulations, coupled to the increasing computational power of novel architectures and integrated with available experimental inputs, allows today exploring the functioning of biological systems with unprecedented accuracy. Indeed, molecular simulations at both the quantum mechanics and molecular mechanics levels are nowadays able to dissect with high confidence the structural and dynamical features of large systems in native-like conditions, up to the point that their mode of action can be modulated in a controlled fashion. These computational chemistry strategies are particularly appealing when applied to pharmaceutically relevant targets. In this chapter, we will present recent successes of computational investigations applied to a broad variety of biochemical systems that are promising or validated targets for drug discovery. In particular, we will show how molecular modelling at the quantum mechanics level is key for revealing the mechanistic details of catalysis in bacterial and viral metallo-enzymes. We will continue by discussing how accurate molecular mechanics-based free energy calculations can provide a new quantitative description of the function of systems of relevance for multidrug resistance in bacteria. In the final part of the chapter, we will show examples where computational and medicinal chemistry is fully integrated with structural and biochemical data to study function and inhibition of target enzymes implicated in cancer and other inflammatory-related diseases. The final goal of these studies is to develop new molecular entities potentially endowed with a desired pharmacological activity. This chapter will therefore define the contribution of emerging approaches and recent advances in the field of computational chemistry for translating the atomic-level understanding of complex biological phenomena into useful information to progress in molecular medicine.


Keywords: Hybrid QM/MM, molecular dynamics, molecular modelling, multiscale modelling, protein ligand interactions, structure-based drug design.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
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      • 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 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 <= 314538714 and j.to_ip >=314538714 )) and ((j.from_date <= 1739835012 and j.to_date >= 1739835012 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 7122) 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 <= 314538714 and j.to_ip >=314538714 )) and ((j.from_date <= 1739835012 and j.to_date >= 1739835012 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 7122) 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 <= 314538714 and j.to_ip >=314538714 )) and ((j.from_date <= 1739835012 and j.to_date >= 1739835012 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 7122)
      650μsalphaeurekaselec_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` = 1688 and `b`.`banner_from_date` <= 1739835012 and `b`.`banner_to_date` >= 1739835012 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.11msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 1688
      • 3: 1739835012
      • 4: 1739835012
      • 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='0a55473dc63f225d42553c855524d857'
      240μsalphaeurekaselec_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
    6Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        u9EqMd4xgYmdlMdCAeFMWQMLttLpQmPn27EwbCcI
        uc_cart_id
        0a55473dc63f225d42553c855524d857
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/7122" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/7122
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
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        request_cookies
        0 of 0
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        response_headers
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        session_attributes
        0 of 0
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-17 23:30:12GET/chapter/7122112198