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Boronic Acid Group: A Cumbersome False Negative Case in the Process of Drug Design.

ABSTRACT: Herein we present, an exhaustive docking analysis considering the case of autotaxin (ATX). HA155, a small molecule inhibitor of ATX, is co-crystallized. In order to further extract conclusions on the nature of the bond formed between the ligands and the amino acid residues of the active site, density functional theory (DFT) calculations were undertaken. However, docking does not provide reproducible results when screening boronic acid derivatives and their binding orientations to protein drug targets. Based on natural bond orbital (NBO) calculations, the formed bond between Ser/Thr residues is characterized more accurately as a polar covalent bond instead of a simple nonpolar covalent one. The presented results are acceptable and could be used in screening as an active negative filter for boron compounds. The hydroxyl groups of amino acids are bonded with the inhibitor's boron atom, converting its hybridization to sp³.

SUBMITTER: Katsamakas S

PROVIDER: S-EPMC6273881 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Boronic Acid Group: A Cumbersome False Negative Case in the Process of Drug Design.

Katsamakas Sotirios S Papadopoulos Anastasios G AG Hadjipavlou-Litina Dimitra D

Molecules (Basel, Switzerland) 20160907 9

Herein we present, an exhaustive docking analysis considering the case of autotaxin (ATX). HA155, a small molecule inhibitor of ATX, is co-crystallized. In order to further extract conclusions on the nature of the bond formed between the ligands and the amino acid residues of the active site, density functional theory (DFT) calculations were undertaken. However, docking does not provide reproducible results when screening boronic acid derivatives and their binding orientations to protein drug ta ...[more]

PMID: 27617984

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Project description:BackgroundVector-borne diseases are major public health concerns worldwide. For many of them, vector control is still key to primary prevention, with control actions planned and evaluated using vector occurrence records. Yet vectors can be difficult to detect, and vector occurrence indices will be biased whenever spurious detection/non-detection records arise during surveys. Here, we investigate the process of Chagas disease vector detection, assessing the performance of the surveillance method used in most control programs--active triatomine-bug searches by trained health agents.Methodology/principal findingsControl agents conducted triplicate vector searches in 414 man-made ecotopes of two rural localities. Ecotope-specific 'detection histories' (vectors or their traces detected or not in each individual search) were analyzed using ordinary methods that disregard detection failures and multiple detection-state site-occupancy models that accommodate false-negative and false-positive detections. Mean (± SE) vector-search sensitivity was ? 0.283 ± 0.057. Vector-detection odds increased as bug colonies grew denser, and were lower in houses than in most peridomestic structures, particularly woodpiles. False-positive detections (non-vector fecal streaks misidentified as signs of vector presence) occurred with probability ? 0.011 ± 0.008. The model-averaged estimate of infestation (44.5 ± 6.4%) was ? 2.4-3.9 times higher than naïve indices computed assuming perfect detection after single vector searches (11.4-18.8%); about 106-137 infestation foci went undetected during such standard searches.Conclusions/significanceWe illustrate a relatively straightforward approach to addressing vector detection uncertainty under realistic field survey conditions. Standard vector searches had low sensitivity except in certain singular circumstances. Our findings suggest that many infestation foci may go undetected during routine surveys, especially when vector density is low. Undetected foci can cause control failures and induce bias in entomological indices; this may confound disease risk assessment and mislead program managers into flawed decision making. By helping correct bias in naïve indices, the approach we illustrate has potential to critically strengthen vector-borne disease control-surveillance systems.

Dataset Information

Boronic Acid Group: A Cumbersome False Negative Case in the Process of Drug Design.

Publications

Boronic Acid Group: A Cumbersome False Negative Case in the Process of Drug Design.

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