FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4229367658> ?p ?o ?g. }

• W4229367658 endingPage "3844" @default.
• W4229367658 startingPage "3829" @default.
• W4229367658 abstract "In drug design, chemical groups are sequentially added to improve a weak-binding fragment into a tight-binding lead molecule. Often, the direction to make these additions is unclear, and there are numerous chemical modifications to choose. Lead development can be guided by crystal structures of the fragment-bound protein, but this alone is unable to capture structural changes like closing or opening of the binding site and any side-chain movements. Accounting for adaptation of the site requires a dynamic approach. Here, we use molecular dynamics calculations of small organic solvents with protein-fragment pairs to reveal the nearest hot spots. These close hot spots show the direction to make appropriate additions and suggest types of chemical modifications that could improve binding affinity. Mixed-solvent molecular dynamics (MixMD) is a cosolvent simulation technique that is well established for finding binding hot spots in active sites and allosteric sites of proteins. We simulated 20 fragment-bound and apo forms of key pharmaceutical targets to map out hot spots for potential lead space. Furthermore, we analyzed whether the presence of a fragment facilitates the probes' binding in the lead space, a type of binding cooperativity. To the best of our knowledge, this is the first use of cosolvent MD conducted with bound inhibitors in the simulation. Our work provides a general framework to extract molecular features of binding sites to choose chemical groups for growing lead molecules. Of the 20 systems, 17 systems were well mapped by MixMD. For the three not-mapped systems, two had lead growth out into solution away from the protein, and the third had very small modifications which indicated no nearby hot spots. Therefore, our lack of mapping in three systems was appropriate given the experimental data (true-negative cases). The simulations are run for very short time scales, making this method tractable for use in the pharmaceutical industry." @default.
• W4229367658 created "2022-05-10" @default.
• W4229367658 creator A5020145710 @default.
• W4229367658 creator A5074146124 @default.
• W4229367658 date "2022-05-09" @default.
• W4229367658 modified "2023-09-23" @default.
• W4229367658 title "Cosolvent Simulations with Fragment-Bound Proteins Identify Hot Spots to Direct Lead Growth" @default.
• W4229367658 cites W1827840064 @default.
• W4229367658 cites W1891528627 @default.
• W4229367658 cites W1895235630 @default.
• W4229367658 cites W1967533757 @default.
• W4229367658 cites W1978367874 @default.
• W4229367658 cites W1982393730 @default.
• W4229367658 cites W1988335148 @default.
• W4229367658 cites W1995206879 @default.
• W4229367658 cites W1997036507 @default.
• W4229367658 cites W2002439304 @default.
• W4229367658 cites W2002665560 @default.
• W4229367658 cites W2003872705 @default.
• W4229367658 cites W2012606436 @default.
• W4229367658 cites W2015688756 @default.
• W4229367658 cites W2019048640 @default.
• W4229367658 cites W2023271753 @default.
• W4229367658 cites W2025458374 @default.
• W4229367658 cites W2031373255 @default.
• W4229367658 cites W2035266068 @default.
• W4229367658 cites W2038533471 @default.
• W4229367658 cites W2039924198 @default.
• W4229367658 cites W2040333979 @default.
• W4229367658 cites W2061562309 @default.
• W4229367658 cites W2066962978 @default.
• W4229367658 cites W2074800090 @default.
• W4229367658 cites W2079953901 @default.
• W4229367658 cites W2095744864 @default.
• W4229367658 cites W2102537419 @default.
• W4229367658 cites W2106140689 @default.
• W4229367658 cites W2126609920 @default.
• W4229367658 cites W2130479394 @default.
• W4229367658 cites W2131424070 @default.
• W4229367658 cites W2135680418 @default.
• W4229367658 cites W2141348757 @default.
• W4229367658 cites W2142489411 @default.
• W4229367658 cites W2143981217 @default.
• W4229367658 cites W2146462263 @default.
• W4229367658 cites W2147993766 @default.
• W4229367658 cites W2148284063 @default.
• W4229367658 cites W2149092467 @default.
• W4229367658 cites W2172242534 @default.
• W4229367658 cites W2172609141 @default.
• W4229367658 cites W2217901364 @default.
• W4229367658 cites W2255447708 @default.
• W4229367658 cites W2286718346 @default.
• W4229367658 cites W2327865165 @default.
• W4229367658 cites W2332712348 @default.
• W4229367658 cites W2340488228 @default.
• W4229367658 cites W2355459424 @default.
• W4229367658 cites W2404280981 @default.
• W4229367658 cites W2440786981 @default.
• W4229367658 cites W2467779447 @default.
• W4229367658 cites W2483704935 @default.
• W4229367658 cites W2521624147 @default.
• W4229367658 cites W2526408712 @default.
• W4229367658 cites W2532216867 @default.
• W4229367658 cites W2550076487 @default.
• W4229367658 cites W2560601914 @default.
• W4229367658 cites W2570397282 @default.
• W4229367658 cites W2588056590 @default.
• W4229367658 cites W2589553742 @default.
• W4229367658 cites W2756301415 @default.
• W4229367658 cites W2770520770 @default.
• W4229367658 cites W2772976883 @default.
• W4229367658 cites W2793082285 @default.
• W4229367658 cites W2796288304 @default.
• W4229367658 cites W2797801723 @default.
• W4229367658 cites W2807907860 @default.
• W4229367658 cites W2886669737 @default.
• W4229367658 cites W2915245694 @default.
• W4229367658 cites W2941542033 @default.
• W4229367658 cites W2944973540 @default.
• W4229367658 cites W2971116291 @default.
• W4229367658 cites W3000292177 @default.
• W4229367658 cites W3132180101 @default.
• W4229367658 cites W984132521 @default.
• W4229367658 doi "https://doi.org/10.1021/acs.jctc.1c01054" @default.
• W4229367658 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35533286" @default.
• W4229367658 hasPublicationYear "2022" @default.
• W4229367658 type Work @default.
• W4229367658 citedByCount "3" @default.
• W4229367658 countsByYear W42293676582022 @default.
• W4229367658 countsByYear W42293676582023 @default.
• W4229367658 crossrefType "journal-article" @default.
• W4229367658 hasAuthorship W4229367658A5020145710 @default.
• W4229367658 hasAuthorship W4229367658A5074146124 @default.
• W4229367658 hasConcept C107824862 @default.
• W4229367658 hasConcept C147597530 @default.
• W4229367658 hasConcept C151730666 @default.
• W4229367658 hasConcept C159467904 @default.
• W4229367658 hasConcept C161624437 @default.

• next