Dataset Information

A poke in the eye: inhibiting HIV-1 protease through its flap-recognition pocket.

ABSTRACT: A novel mechanism of inhibiting HIV-1 protease (HIVp) is presented. Using computational solvent mapping to identify complementary interactions and the Multiple Protein Structure method to incorporate protein flexibility, we generated a receptor-based pharmacophore model of the flexible flap region of the semiopen, apo state of HIVp. Complementary interactions were consistently observed at the base of the flap, only within a cleft with a specific structural role. In the closed, bound state of HIVp, each flap tip docks against the opposite monomer, occupying this cleft. This flap-recognition site is filled by the protein and cannot be identified using traditional approaches based on bound, closed structures. Virtual screening and dynamics simulations show how small molecules can be identified to complement this cleft. Subsequent experimental testing confirms inhibitory activity of this new class of inhibitor. This may be the first new inhibitor class for HIVp since dimerization inhibitors were introduced 17 years ago.

SUBMITTER: Damm KL

PROVIDER: S-EPMC2859825 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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A poke in the eye: inhibiting HIV-1 protease through its flap-recognition pocket.

Damm Kelly L KL Ung Peter M U PM Quintero Jerome J JJ Gestwicki Jason E JE Carlson Heather A HA

Biopolymers 20080801 8

A novel mechanism of inhibiting HIV-1 protease (HIVp) is presented. Using computational solvent mapping to identify complementary interactions and the Multiple Protein Structure method to incorporate protein flexibility, we generated a receptor-based pharmacophore model of the flexible flap region of the semiopen, apo state of HIVp. Complementary interactions were consistently observed at the base of the flap, only within a cleft with a specific structural role. In the closed, bound state of HIV ...[more]

PMID: 18381626

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Project description:BackgroundCriminal associates such as terrorist members are likely to deny knowing members of their network when questioned by police. Eye tracking research suggests that lies about familiar faces can be detected by distinct markers of recognition (e.g. fewer fixations and longer fixation durations) across multiple eye fixation parameters. However, the effect of explicit eye movement strategies to concealed recognition on such markers has not been examined. Our aim was to assess the impact of fixed-sequence eye movement strategies (across the forehead, ears, eyes, nose, mouth and chin) on markers of familiar face recognition. Participants were assigned to one of two groups: a standard guilty group who were simply instructed to conceal knowledge but with no specific instructions on how to do so; and a countermeasures group who were instructed to look at every familiar and unfamiliar face in the same way by executing a consistent sequence of fixations.ResultsIn the standard guilty group, lies about recognition of familiar faces showed longer average fixation durations, a lower proportion of fixations to the inner face regions, and proportionately more viewing of the eyes than honest responses to genuinely unknown faces. In the countermeasures condition, familiar face recognition was detected by longer fixations durations, fewer fixations to the inner regions of the face, and fewer interest areas of the face viewed. Longer fixation durations were a consistent marker of recognition across both conditions for most participants; differences were detectable from the first fixation.ConclusionThe results suggest that individuals can exert a degree of executive control over fixation patterns but that: the eyes are particularly attention-grabbing for familiar faces; the more viewers look around the face, the more they give themselves away; and attempts to deploy the same fixation patterns to familiar and unfamiliar faces were unsuccessful. The results suggest that the best strategy for concealing recognition might be to keep the eyes fixated in the centre of the screen but, even then, recognition is apparent in longer fixation durations. We discuss potential optimal conditions for detecting concealed knowledge of faces.

Dataset Information

A poke in the eye: inhibiting HIV-1 protease through its flap-recognition pocket.

Publications

A poke in the eye: inhibiting HIV-1 protease through its flap-recognition pocket.

Similar Datasets

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