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Partial-occupancy binders identified by the Pan-Dataset Density Analysis method offer new chemical opportunities and reveal cryptic binding sites.

ABSTRACT: Crystallographic fragment screening uses low molecular weight compounds to probe the protein surface and although individual protein-fragment interactions are high quality, fragments commonly bind at low occupancy, historically making identification difficult. However, our new Pan-Dataset Density Analysis method readily identifies binders missed by conventional analysis: for fragment screening data of lysine-specific demethylase 4D (KDM4D), the hit rate increased from 0.9% to 10.6%. Previously unidentified fragments reveal multiple binding sites and demonstrate: the versatility of crystallographic fragment screening; that surprisingly large conformational changes are possible in crystals; and that low crystallographic occupancy does not by itself reflect a protein-ligand complex's significance.

SUBMITTER: Pearce NM

PROVIDER: S-EPMC5336473 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Partial-occupancy binders identified by the Pan-Dataset Density Analysis method offer new chemical opportunities and reveal cryptic binding sites.

Pearce Nicholas M NM Bradley Anthony R AR Krojer Tobias T Marsden Brian D BD Deane Charlotte M CM von Delft Frank F

Structural dynamics (Melville, N.Y.) 20170228 3

Crystallographic fragment screening uses low molecular weight compounds to probe the protein surface and although individual protein-fragment interactions are high quality, fragments commonly bind at low occupancy, historically making identification difficult. However, our new Pan-Dataset Density Analysis method readily identifies binders missed by conventional analysis: for fragment screening data of lysine-specific demethylase 4D (KDM4D), the hit rate increased from 0.9% to 10.6%. Previously u ...[more]

PMID: 28345007

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Project description:BackgroundThe prevalence of diabetes mellitus (DM) is increasing rapidly worldwide. Simultaneously, technological advances are offering new opportunities for better management of type 1 diabetes mellitus (T1DM). Telemetry, the remote acquisition of patient data via a telecommunication system, is a promising field of application in eHealth and is rapidly gaining importance.ObjectiveThe aim of this study was to summarize the current evidences available on the effectiveness of telemetric approaches in T1DM management. This systematic meta-review examined different types of interventions of the technologies used in communication between health care professionals and patients as well as the key outcomes.MethodsWe performed a systematic search in Web of Science Core Collection, EMBASE, Cochrane Library, MEDLINE via PubMed, and CINAHL databases in April 2020 with regard to the effectiveness of telemetric interventions for T1DM. We classified the interventions into 4 categories according to the technology used: (1) real-time video communication, (2) real-time audio communication, (3) asynchronous communication, and (4) combined forms of communication (real-time and asynchronous). We considered various study designs such as systematic reviews, clinical trials, meta-analyses, and randomized controlled trials and focused on the key outcomes. Additionally, a funnel plot based on hemoglobin A1c (HbA1c) values and different quality assessments were performed.ResultsWe identified 17 (6 high quality and 9 moderate quality) eligible publications: randomized controlled trials (n=9), systematic reviews and meta-analyses (n=5), cohort studies (n=2), and qualitative publications (n=1). Of 12 studies, 8 (67%) indicated a (significant or nonsignificant) reduction in HbA1c levels; 65% (11/17) of the studies reported overall (mildly) positive effects of telemetric interventions by addressing all the measured outcomes. Asynchronous interventions were the most successful for patients diagnosed with T1DM, but no technology was clearly superior. However, there were many nonsignificant results and not sustained effects, and in some studies, the control group benefited from telemetric support or increased frequency of contacts.ConclusionsBased on the currently available literature, this systematic meta-review shows that telemetric interventions cause significant reduction in HbA1c levels and result in overall positive effects in T1DM management. However, more specified effects of telemetric approaches in T1DM management should be analyzed in detail in larger cohorts.

Dataset Information

Partial-occupancy binders identified by the Pan-Dataset Density Analysis method offer new chemical opportunities and reveal cryptic binding sites.

Publications

Partial-occupancy binders identified by the Pan-Dataset Density Analysis method offer new chemical opportunities and reveal cryptic binding sites.

Similar Datasets

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