[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-657139-105":59,"doc-detail-657139-en":122},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":115,"head_meta":117,"extra_data":119,"updated_unix":121},105,"en","molecular-modelling-overcoming-the-limitations-of-chemical-structure-drug-discovery","Molecular modelling - Overcoming the limitations of chemical structure - drug discovery","","Discusses how drug discovery is hindered by overreliance on 2D “atom and bond” and Markush chemical structure representations. Explains that biological targets recognize molecular property fields rather than 2D structural make-up, enabling faster comparison and reducing major obstacles in identifying activity. Describes the impact on “chemotype jumps,” including long timelines, high cost, and serendipity, and argues for three-dimensional conformational understanding in protein selectivity.",{"@graph":69,"@context":114},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/molecular-modelling-overcoming-the-limitations-of-chemical-structure-drug-discovery/657139/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/molecular-modelling-overcoming-the-limitations-of-chemical-structure-drug-discovery/657139.png","ImageObject",300,407,{"name":92,"@type":93},"bocahgabuttt","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-10-26",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108],{"name":109,"@type":110,"acceptedAnswer":111},"How does 3D molecular behavior improve understanding of protein selectivity?","Question",{"text":112,"@type":113},"Molecules are three-dimensional and change shape quickly, and these conformational and volume changes drive selectivity. The target recognizes complementary shapes when the molecule binds, offering a more accurate basis for predicting interaction and behavior.","Answer","https://schema.org",{"og:url":83,"og:type":116,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":118,"canonical":83},"index,follow",{"doc_id":120,"site_id":62},657139,1793100794,{"code":4,"msg":5,"data":123},{"doc_id":120,"user_id":124,"nickname":92,"user_avatar":125,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":126,"file_id":127,"file_url":128,"file_type":129,"file_size":130,"view_count":19,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":29,"language":131,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":132,"faqs":133,"seo_title":134,"seo_description":67,"update_tm":135,"read_time":136},962094248839,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","Chemical  \nstructure:Layout  \n1  \n26/6/09  \n13:37  \nPage  \n58  \nMolecular modelling  \nOvercoming the limitations of chemical structure  \nThe pharmaceutical business has been profoundly hampered by a ubiquitous and unexpected obstacle – the way it draws its chemical compounds. Scientists, patent agents and business decision makers from R&D, safety, and in-licensing are locked into a world of 2D ‘atom and bond’ and Markush representations of the molecular structure of compounds. Biological targets do not recognise a drug’s structural make-up.They respond instead to the properties around the drug that are generated by the structure.We can now generate and compare these property fields and show how they alone eliminate the largest impediments to drug discovery – the time and cost of evaluating activity and the serendipity involved in jumping from one chemical class to another for resolving patent issues, biological cross-reactions, ADMET and alternative clinical applications.  \nBy DrAndy Vinter, Dr Steve Gardner and Dr Sally Rose  \nIn the pharmaceutical world, scientists routine  \nly use 2D structural likeness to indicate similar  \nbiological action. 2D ‘atom and bond’ representation such as those shown in Figure 1 are, after all, the de facto language of chemistry. So why question the authority of this representation after applying it for so long on all aspects of drug discovery from activity enhancement to toxicity and from patent application to safety issues?  \nThe reason is simple – it has a serious limitation that inhibits our ability to discover, protect and bring to market new drugs. That limitation is familiar to most chemists. We have known for many years that very different structures can act atthe same biological target to effect the same biological action. The obvious conclusion must be that chemical structure – atoms linked by bonds –  \nis not what is recognised by a biological target.  \nMolecule A and molecule B in Figure 1 bear no structural relationship to one other and yet molecule B mimics molecule A – both are able to occupy the same site on a common target (see Figure 4) . The corollary is also often true; very closely related derivative structures regularly exhibit very diverse activities at a given target.  \nThis inability of 2D structure to describe a compound’s activity has profound consequences. Chemists are routinely required to make ‘chemotype jumps’ to move from one chemical class, all members of which have one or more common structural features, to another. Such chemotype jumps are vital if structures are to be novel and patentable, if pre-clinical ADME (absorption, distribution, metabolism, and excretion), safety and  \n58 Drug Discovery World Summer 2009  \nChemical  \nstructure:Layout  \n1  \n26/6/09  \n13:37  \nPage  \n59  \nMolecular modelling  \ntoxicity problems are to be overcome and FDA requirements satisfied. It often takes chemists up to three years to make a single chemotype jump and the process is essentially serendipitous as the structure offers no clues as to the likely activity of the compounds. This obviously requires a huge investment in cost and time and there is always a risk that no such alternate chemotype with appropriate activity will be found.  \nMany chemotype jumps are required in the long haul from early hit to marketable drug. By the late 1980s, so costly and time-consuming had this process become that companies embraced the ideas of high throughput chemistry and screening in the hope that applying these parallel processes to tens of thousands of molecules, they would alleviate the‘chemotype trap’. In the event, it not only reduced the chances of chemical novelty but left them to drown in a sea of irresolvable data.  \nThe alternative to chemical structure  \nBefore discussing how molecules recognise eachother, we must remind ourselves that molecules are three-dimensional and exist in a specific shape (or conformation) . To make matters more complex, most molecules change their shape an","cbCain0OIAWzkrrQ","https://ap.wps.com/l/cbCain0OIAWzkrrQ","pdf",537867,"English","# Molecular modelling\n## Limitations of 2D chemical structure\n## Why biological targets do not rely on 2D make-up\n## Consequences: chemotype jumps and delays\n## The alternative: molecular recognition in 3D conformations\n## Lock-and-key and molecular interaction surfaces","[{\"question\":\"How does 3D molecular behavior improve understanding of protein selectivity?\",\"answer\":\"Molecules are three-dimensional and change shape quickly, and these conformational and volume changes drive selectivity. The target recognizes complementary shapes when the molecule binds, offering a more accurate basis for predicting interaction and behavior.\"}]","Molecular modelling - Overcoming the limitations of chemical structure - drug discovery | PDF",1792974754,15]