Frontiers in Medicinal Chemistry

Volume: 7

PfDHFR Enzyme Inhibitors: Rational Design Using Pharmacoinformatic Tools

Author(s): Sheenu Abbat, Shweta Bhagat and Prasad V. Bharatam

Pp: 228-273 (46)

DOI: 10.2174/9781608059706115070009

* (Excluding Mailing and Handling)

Abstract

Malaria is recognized as the most dangerous disease originating from parasites. Plasmodium falciparum dihydrofolate reductase (PfDHFR) is one of the important targets for anti-malarial drug design. All the reported anti-folates show drug resistance. Mutations in the active-site of PfDHFR enzyme, particularly at 16, 51, 59, 108, and 164 residues, are responsible for the observed resistance. The new strategies for anti-malarial drug discovery include design of leads which are effective against both wild type and mutant PfDHFR. Recent efforts in this direction lead to the identification of P218 as an important lead compound. In addition a set of guanylthiourea derivatives were also reported. Rational lead design strategies are being adopted for the design of PfDHFR inhibitors as anti-malarial agents. In this update, a review of the computeraided drug design which was adopted over the past decade, in the design of PfDHFR inhibitors, are elaborated. Efforts based on molecular docking, pharmacophore mapping, QSAR, homology modeling, and quantum chemical studies are discussed in detail. Special emphasis is given to the importance of drug action while discussing the pharmacoinformatic approaches. In future the rational methods of lead design and lead optimization are expected to increase because sufficient knowledge is already generated on the structural aspects of PfDHFR and its possible inhibitors are already available.


Keywords: Antifolates, anti-malarial, molecular docking, molecular dynamics, P. falciparum DHFR inhibitors, pharmacoinformatic tools and X-ray crystallographic analysis, pharmacophore mapping, QSAR, quadruple mutant enzyme, quantum medicinal chemistry, structure based drug design.

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      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1518
      • 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 <= 316548017 and j.to_ip >=316548017 )) and ((j.from_date <= 1739847390 and j.to_date >= 1739847390 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 7212) 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 <= 316548017 and j.to_ip >=316548017 )) and ((j.from_date <= 1739847390 and j.to_date >= 1739847390 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 7212) 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 <= 316548017 and j.to_ip >=316548017 )) and ((j.from_date <= 1739847390 and j.to_date >= 1739847390 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 7212)
      640μsalphaeurekaselec_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` = 1696 and `b`.`banner_from_date` <= 1739847390 and `b`.`banner_to_date` >= 1739847390 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.01msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 1696
      • 3: 1739847390
      • 4: 1739847390
      • 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='55aa3b14615a74b5cd28437356127a4d'
      160μsalphaeurekaselec_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
    11Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        VnliGWrhMIqlcVdDXgYNSYYMVncQWQ39WuQAPPid
        uc_cart_id
        55aa3b14615a74b5cd28437356127a4d
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/7212" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/7212
        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=eyJpdiI6IlU5dy9aMWJCUFhCSHl1OEsvRE1XZ2c9PSIsInZhbHVlIjoiV0VwUFpUazd1SWd1WWRJTnk3cFlJS1pEeGdCVDNQOXZHMnpFR1Q5Z1ZVOD0iLCJtYWMiOiI0ZGI0NmVkNjE1ZDczZWRmOWY5MDhhNTE3ZGJiZmMzNDlkZjAzZGQ5Y2I1Njc3MGZkOWQ2YWE1Mzc0YjRjNWFhIiwidGFnIjoiIn0%3Dwayfindertarget=eyJpdiI6IlU5dy9aMWJCUFhCSHl1OEsvRE1XZ2c9PSIsInZhbHVlIjoiV0VwUFpUazd1SWd1WWRJTnk3cFlJS1pEeGdCVDNQOXZHMnpFR1Q5Z1ZVOD0iLCJtYWMiOiI0ZGI0NmVkNjE1ZDcz" ] "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 02:56:30 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlhTbk95am4rZmsyMDBVeE1WV2pHM3c9PSIsInZhbHVlIjoiR0tzY1V4SHN6aVFJWWEzd3JyWElBc2VqRmh5cE1rcmNOZHh1WUR6WnhFQUhpL3hJUTNnTHJpMHBUWk1nM0ZuU3hPR2NMQyttTzA3dGdHMWpORnBLR0hvVWpyakJDVzlSMEdZSWZBOFpCRnQwc25sSS9FYXFOby9ERVVWWnBpWXgiLCJtYWMiOiJlNWJhZDI5YTU5NmRkZTlkNjYwZDA2YWI1NzA0ZTA0YTBmNzc2NzczYWNjYWM2ZjBhOGI5Y2EyNWI2OWM0NGZjIiwidGFnIjoiIn0%3D; expires=Thu, 20 Feb 2025 14:56:30 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IlhTbk95am4rZmsyMDBVeE1WV2pHM3c9PSIsInZhbHVlIjoiR0tzY1V4SHN6aVFJWWEzd3JyWElBc2VqRmh5cE1rcmNOZHh1WUR6WnhFQUhpL3hJUTNnTHJpMHBUWk1nM0ZuU3hPR2NMQ" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImRzcHN2aWhQSGk5OTFlVzJGbnk3eWc9PSIsInZhbHVlIjoiZXZhSXE0Snp0T2tXa3Job2szUy9BSEJyS3JWeGdXOE1nd0t4eHI4Yk5qWmgxMDVmMThQM3MxZy80UnE3YUgwRjhoZUo1dEJ3VjRCRFI0b3R2WFk1TTBkN1BjT1VBeit0M3dxRUo2d21TdjJOK29qTTFQZk5yendlQWpaaytpUGIiLCJtYWMiOiJmZjg3ODQyM2M1MjdhMmFiNzllZmY4ZTQxZGQ3NDc3YTdlNDk5NTJkNjA1YWM1MDVhODQ0MWI2Mzc5NTZmYjZmIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6ImRzcHN2aWhQSGk5OTFlVzJGbnk3eWc9PSIsInZhbHVlIjoiZXZhSXE0Snp0T2tXa3Job2szUy9BSEJyS3JWeGdXOE1nd0t4eHI4Yk5qWmgxMDVmMThQM3MxZy8" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlhTbk95am4rZmsyMDBVeE1WV2pHM3c9PSIsInZhbHVlIjoiR0tzY1V4SHN6aVFJWWEzd3JyWElBc2VqRmh5cE1rcmNOZHh1WUR6WnhFQUhpL3hJUTNnTHJpMHBUWk1nM0ZuU3hPR2NMQyttTzA3dGdHMWpORnBLR0hvVWpyakJDVzlSMEdZSWZBOFpCRnQwc25sSS9FYXFOby9ERVVWWnBpWXgiLCJtYWMiOiJlNWJhZDI5YTU5NmRkZTlkNjYwZDA2YWI1NzA0ZTA0YTBmNzc2NzczYWNjYWM2ZjBhOGI5Y2EyNWI2OWM0NGZjIiwidGFnIjoiIn0%3D; expires=Thu, 20-Feb-2025 14:56:30 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IlhTbk95am4rZmsyMDBVeE1WV2pHM3c9PSIsInZhbHVlIjoiR0tzY1V4SHN6aVFJWWEzd3JyWElBc2VqRmh5cE1rcmNOZHh1WUR6WnhFQUhpL3hJUTNnTHJpMHBUWk1nM0ZuU3hPR2NMQ" 1 => "alphaeurekaselectnet_session=eyJpdiI6ImRzcHN2aWhQSGk5OTFlVzJGbnk3eWc9PSIsInZhbHVlIjoiZXZhSXE0Snp0T2tXa3Job2szUy9BSEJyS3JWeGdXOE1nd0t4eHI4Yk5qWmgxMDVmMThQM3MxZy80UnE3YUgwRjhoZUo1dEJ3VjRCRFI0b3R2WFk1TTBkN1BjT1VBeit0M3dxRUo2d21TdjJOK29qTTFQZk5yendlQWpaaytpUGIiLCJtYWMiOiJmZjg3ODQyM2M1MjdhMmFiNzllZmY4ZTQxZGQ3NDc3YTdlNDk5NTJkNjA1YWM1MDVhODQ0MWI2Mzc5NTZmYjZmIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6ImRzcHN2aWhQSGk5OTFlVzJGbnk3eWc9PSIsInZhbHVlIjoiZXZhSXE0Snp0T2tXa3Job2szUy9BSEJyS3JWeGdXOE1nd0t4eHI4Yk5qWmgxMDVmMThQM3MxZy8" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "VnliGWrhMIqlcVdDXgYNSYYMVncQWQ39WuQAPPid" "uc_cart_id" => "55aa3b14615a74b5cd28437356127a4d" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/7212" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-18 02:56:30GET/chapter/72121121913