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Biology subjects

Chan, A. W. E.

Publications and source records attributed to Chan, A. W. E..

3 recordsLinked to original sources

Machine Learning Prediction of HIV1 Drug Resistance against Integrase Strand Transfer Inhibitors

Infection caused by the human immunodeficiency virus (HIV) can be effectively treated using antiretroviral therapy (ART). One such therapy involves drugs that target the HIV integrase. However, this has resulted in the development of resistant associated mutations (RAMs). This investigation aims to create a machine learning model to classify an input protein sequence of HIV integrase as resistant or non-resistant towards the five approved integrase strand inhibitors (INSTIs). The training data consists of protein sequences along with the associated biological features of each residue: its presence in the drug binding site, secondary structure, solvent accessibility and mutation frequency. A logistic regression model was developed and from this model, key residues which contribute towards drug resistance were identified, including several known RAMs. The model performance was on a par with other similar studies that used for classifiers with more complex architectures. The approach described here could be adapted to other resistance-prone diseases.

bioinformatics↗

Inhibition of GEF-H1-RhoA signaling in inflammation with a stapled peptide mimicry of the RhoA67-78 helix

Guanine exchange factors (GEFs) are considered hard to drug with conventional small molecules, they lack conventional deep binding pockets and binding ligands are seldom reported. Here we report the design of a stapled peptide stP5 targeting the interaction between cytoskeletal regulator RhoA GTPase and its activator guanine exchange factor H1 (GEF-H1). StP5 is a modified RhoA mimic based on a previously identified bioactive -helical epitope to GEF-H1. StP5 effectively inhibits GEF-H1-induced morphological and transcriptional changes in cellular models for inflammation and does not affect the related GEF p114RhoGEF (ARHGEF18). StP5 peptide is approximately 100 fold more active in cellular assays than the unstapled P5 peptide. We provide a bioinformatic analysis of the stP5 bindings site in different GEFs, providing a basis for this selectivity. The GEF-H1 inhibitor stP5 represents a step towards fully drugging GEF-H1. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/624118v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@d783b3org.highwire.dtl.DTLVardef@10798b2org.highwire.dtl.DTLVardef@1ba0817org.highwire.dtl.DTLVardef@693367_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

Deciphering the co-evolutionary dynamics of L2 β-lactamases via Deep learning

L2 {beta}-lactamases, a serine-based class A {beta}-lactamases expressed by Stenotrophomonas maltophilia plays a pivotal role in antimicrobial resistance. However, limited studies have been conducted on these important enzymes. To understand the co-evolutionary dynamics of L2 {beta}-lactamase, innovative computational methodologies, including adaptive sampling molecular dynamics simulations, and deep learning methods (convolutional variational autoencoders and BindSiteS-CNN) explored conformational changes and correlations within the L2 {beta}-lactamase family together with other representative class A enzymes including SME-1 and KPC-2. This work also investigated the potential role of hydrophobic nodes and binding site residues in facilitating the functional mechanisms. The convergence of analytical approaches utilized in this effort yielded comprehensive insights into the dynamic behaviour of the {beta}-lactamases, specifically from an evolutionary standpoint. In addition, this analysis presents a promising approach for understanding how the class A {beta}-lactamases evolve in response to environmental pressure and establishes a theoretical foundation for forthcoming endeavours in drug development aimed at combating antimicrobial resistance. SynopsisDeep learning is used to reveal the dynamic co-evolutionary patterns of L2 {beta}-lactamases. O_LIAnalysis of hydrophobic nodes and binding site residues provides a detailed understanding of both local and global dynamic evolution, which explain the functional divergences. C_LIO_LIThe employment of two distinct deep learning models, the Convolutional Variational Autoencoder (CVAE) and BindSiteS-CNN, facilitates the investigation of conformational shifts, thereby depicting the dynamic evolution of L2 {beta}-lactamases. C_LIO_LIThe effectiveness of CVAE and BindSiteS-CNN in dynamic classification is corroborated with selected features. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/575584v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1db15forg.highwire.dtl.DTLVardef@168043eorg.highwire.dtl.DTLVardef@1eebb96org.highwire.dtl.DTLVardef@5d8019_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗