USING PROTEIN STRUCTURE TO COMBAT ANTIMICROBIAL RESISTANCE

Insights from Spatial Measures of Intolerance to Identifying Pathogenic Variants in Developmental and Epileptic Encephalopathies

Michael Silk, Alex de Sá, Moshe Olshansky, David B Ascher

2023-03-07

<jats:p>Developmental and epileptic encephalopathies (DEEs) are a group of epilepsies with early onset and severe symptoms that so..

CSM-Toxin: A Web-Server for Predicting Protein Toxicity.

Vladimir Morozov, Carlos HM Rodrigues, David B Ascher

2023-01-28

Biologics are one of the most rapidly expanding classes of therapeutics, but can be associated with a range of toxic properties. I..

embryoTox: Using Graph-Based Signatures to Predict the Teratogenicity of Small Molecules

Raghad Aljarf, Simon Tang, Douglas EV Pires, David B Ascher

2023-01-03

Teratogenic drugs can lead to extreme fetal malformation and consequently critically influence the fetus's health, yet the teratog..

DockNet: high-throughput protein-protein interface contact prediction.

Nathan P Williams, Carlos HM Rodrigues, Jia Truong, David B Ascher, Jessica K Holien

2023-01-01

MOTIVATION: Over 300 000 protein-protein interaction (PPI) pairs have been identified in the human proteome and targeting these is..

Using Graph-Based Signatures to Guide Rational Antibody Engineering.

David B Ascher, Lisa M Kaminskas, Yoochan Myung, Douglas EV Pires

2023-01-01

Antibodies are essential experimental and diagnostic tools and as biotherapeutics have significantly advanced our ability to treat..

A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism.

Shridhar Parthasarathy, Sarah McKeown Ruggiero, Antoinette Gelot, Fernanda C Soardi, Bethânia FR Ribeiro, Douglas EV Pires, David B Ascher, Alain Schmitt, Caroline Rambaud, Alfonso Represa, Hongbo M Xie, Laina Lusk, Olivia Wilmarth, Pamela Pojomovsky McDonnell, Olivia A Juarez, Alexandra N Grace, Julien Buratti, Cyril Mignot, Domitille Gras, Caroline Nava

2022-12-01

Heterozygous pathogenic variants in DNM1 cause developmental and epileptic encephalopathy (DEE) as a result of a dominant-negative..

A structural biology community assessment of AlphaFold2 applications.

Mehmet Akdel, Douglas EV Pires, Eduard Porta Pardo, Jürgen Jänes, Arthur O Zalevsky, Bálint Mészáros, Patrick Bryant, Lydia L Good, Roman A Laskowski, Gabriele Pozzati, Aditi Shenoy, Wensi Zhu, Petras Kundrotas, Victoria Ruiz Serra, Carlos HM Rodrigues, Alistair S Dunham, David Burke, Neera Borkakoti, Sameer Velankar, Adam Frost

2022-11-01

Most proteins fold into 3D structures that determine how they function and orchestrate the biological processes of the cell. Recen..

kinCSM: Using graph-based signatures to predict small molecule CDK2 inhibitors

Yunzhuo Zhou, Raghad Al-Jarf, Azadeh Alavi, Thanh Binh Nguyen, Carlos HM Rodrigues, Douglas E Pires, David B Ascher

2022-11-01

Protein phosphorylation acts as an essential on/off switch in many cellular signaling pathways. This has led to ongoing interest i..

cardioToxCSM: A Web Server for Predicting Cardiotoxicity of Small Molecules

Saba Iftkha, Alex GC de Sa, Joao PL Velloso, Raghad Aljarf, Douglas EV Pires, David B Ascher

2022-10-11

The design of novel, safe, and effective drugs to treat human diseases is a challenging venture, with toxicity being one of the ma..

CSM-peptides: A computational approach to rapid identification of therapeutic peptides

Carlos HM Rodrigues, Anjali Garg, David Keizer, Douglas E Pires, David B Ascher

2022-10-01

Peptides are attractive alternatives for the development of new therapeutic strategies due to their versatility and low complexity..

Identifying the molecular drivers of ALS-implicated missense mutations

Stephanie Portelli, Amanda Albanaz, Douglas Eduardo Valente Pires, David Benjamin Ascher

2022-09-30

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressively fatal, neurodegenerative disease associated with both motor and..

HGDiscovery: An online tool providing functional and phenotypic information on novel variants of homogentisate 1,2- dioxigenase

Malancha Karmakar, Vittoria Cicaloni, Carlos HM Rodrigues, Ottavia Spiga, Annalisa Santucci, David B Ascher

2022-09-09

Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in the body. Affected..

VIVID A Web Application for Variant Interpretation and Visualization in Multi-dimensional Analyses

Swapnil Tichkule, Yoochan Myung, Myo T Naung, Brendan RE Ansell, Andrew J Guy, Namrata Srivastava, Somya Mehra, Simone M Caccio, Ivo Mueller, Alyssa E Barry, Cock van Oosterhout, Bernard Pope, David B Ascher, Aaron R Jex

2022-09-01

Large-scale comparative genomics- and population genetic studies generate enormous amounts of polymorphism data in the form of DNA..

toxCSM: comprehensive prediction of small molecule toxicity profiles

Alex GC de Sa, Yangyang Long, Stephanie Portelli, Douglas E Pires, David B Ascher

2022-08-23

Drug discovery is a lengthy, costly and high-risk endeavour that is further convoluted by high attrition rates in later developmen..

Evaluating hierarchical machine learning approaches to classify biological databases

Pamela M Rezende, Joicymara S Xavier, David B Ascher, Gabriel R Fernandes, Douglas E Pires

2022-06-21

The rate of biological data generation has increased dramatically in recent years, which has driven the importance of databases as..

Understanding and predicting the functional consequences of missense mutations in BRCA1 and BRCA2.

Raghad Aljarf, Mengyuan Shen, Douglas EV Pires, David B Ascher

2022-06-21

BRCA1 and BRCA2 are tumour suppressor genes that play a critical role in maintaining genomic stability via the DNA repair mechanis..

Structural landscapes of PPI interfaces

Carlos HM Rodrigues, Douglas E Pires, Tom L Blundell, David B Ascher

2022-06-02

Proteins are capable of highly specific interactions and are responsible for a wide range of functions, making them attractive in ..

CSM-Potential: mapping protein interactions and biological ligands in 3D space using geometric deep learning

Carlos HM Rodrigues, David B Ascher

2022-05-24

Recent advances in protein structural modelling have enabled the accurate prediction of the holo 3D structures of almost any prote..

Systematic evaluation of computational tools to predict the effects of mutations on protein stability in the absence of experimental structures

Qisheng Pan, Thanh Binh Nguyen, David B Ascher, Douglas E Pires

2022-03-10

Changes in protein sequence can have dramatic effects on how proteins fold, their stability and dynamics. Over the last 20 years, ..

cropCSM: designing safe and potent herbicides with graph-based signatures

Douglas E Pires, Keith A Stubbs, Joshua S Mylne, David B Ascher

2022-02-24

Herbicides have revolutionised weed management, increased crop yields and improved profitability allowing for an increase in world..

Known allosteric proteins have central roles in genetic disease

Gyoergy Abrusan, David B Ascher, Michael Inouye

2022-02-01

Allostery is a form of protein regulation, where ligands that bind sites located apart from the active site can modify the activit..

Oxidative desulfurization pathway for complete catabolism of sulfoquinovose by bacteria

Mahima Sharma, James P Lingford, Marija Petricevic, Alexander JD Snow, Yunyang Zhang, Michael A Jarva, Janice W-Y Mui, Nichollas E Scott, Eleanor C Saunders, Ruwan Epa, Bruna M da Silva, Douglas EV Pires, David B Ascher, Malcolm J McConville, Gideon J Davies, Spencer J Williams, Ethan D Goddard-Borger

2022-01-25

Catabolism of sulfoquinovose (SQ; 6-deoxy-6-sulfoglucose), the ubiquitous sulfosugar produced by photosynthetic organisms, is an i..

CSM-carbohydrate: protein-carbohydrate binding affinity prediction and docking scoring function

Binh Nguyen Thanh, Douglas E Pires, David B Ascher

2022-01-17

Protein-carbohydrate interactions are crucial for many cellular processes but can be challenging to biologically characterise. To ..

epitope3D: a machine learning method for conformational B-cell epitope prediction

Bruna Moreira da Silva, YooChan Myung, David B Ascher, Douglas E Pires

2022-01-17

The ability to identify antigenic determinants of pathogens, or epitopes, is fundamental to guide rational vaccine development and..

A bias of Asparagine to Lysine mutations in SARS-CoV-2 outside the receptor binding domain affects protein flexibility.

Jennifer C Boer, Qisheng Pan, Jessica K Holien, Thanh-Binh Nguyen, David B Ascher, Magdalena Plebanski

2022-01-09

INTRODUCTION: COVID-19 pandemic has been threatening public health and economic development worldwide for over two years. Compared..

Bioinformatics Approaches to Predict Mutation Effects in the Binding Site of the Proangiogenic Molecule CD93.

Vittoria Cicaloni, Malancha Karmakar, Luisa Frusciante, Francesco Pettini, Anna Visibelli, Maurizio Orlandini, Federico Galvagni, Maurizio Mongiat, Michael Silk, Federica Nardi, David Ascher, Annalisa Santucci, Ottavia Spiga

2022-01-01

The transmembrane glycoprotein CD93 has been identified as a potential new target to inhibit tumor angiogenesis. Recently, Multime..

pdCSM-PPI: Using Graph-Based Signatures to Identify ProteinProtein Interaction Inhibitors

Carlos HM Rodrigues, Douglas E Pires, David B Ascher

2021-11-22

Protein-protein interactions are promising sites for development of selective drugs; however, they have generally been viewed as c..

mmCSM-NA: accurately predicting effects of single and multiple mutations on protein nucleic acid binding affinity

Binh Nguyen Thanh, Yoochan Myung, Alex GC de Sa, Douglas E Pires, David B Ascher

2021-11-17

While protein-nucleic acid interactions are pivotal for many crucial biological processes, limited experimental data has made the ..

CSM-AB: graph-based antibody-antigen binding affinity prediction and docking scoring function

Yoochan Myung, Douglas E Pires, David B Ascher

2021-11-04

MOTIVATION: Understanding antibody-antigen interactions is key to improving their binding affinities and specificities. While expe..

A novel deep intronic variant strongly associates with Alkaptonuria

Chien-Yi Lai, I-Jung Tsai, Pao-Chin Chiu, David B Ascher, Yin-Hsiu Chien, Yu-Hsuan Huang, Yi-Lin Lin, Wuh-Liang Hwu, Ni-Chung Lee

2021-10-22

Alkaptonuria is a rare autosomal recessive inherited disorder of tyrosine metabolism, which causes ochronosis, arthropathy, cardia..

Structure-guided machine learning prediction of drug resistance mutations in Abelson 1 kinase

Yunzhuo Zhou, Stephanie Portelli, Megan Pat, Carlos HM Rodrigues, Nguyen Thanh-Binh, Douglas E Pires, David B Ascher

2021-10-01

Kinases play crucial roles in cellular signalling and biological processes with their dysregulation associated with diseases, incl..

TSMDA: Target and symptom-based computational model for miRNA-disease-association prediction

Korawich Uthayopas, Alex GC de Sa, Azadeh Alavi, Douglas E Pires, David B Ascher

2021-09-25

The emergence of high-throughput sequencing techniques has revealed a primary role of microRNAs (miRNAs) in a wide range of diseas..

Deep learning in diabetic foot ulcers detection: A comprehensive evaluation

Moi Hoon Yap, Ryo Hachiuma, Azadeh Alavi, Raphael Brungel, Bill Cassidy, Manu Goyal, Hongtao Zhu, Johannes Ruckert, Moshe Olshansky, Xiao Huang, Hideo Saito, Saeed Hassanpour, Christoph M Friedrich, David Ascher, Anping Song, Hiroki Kajita, David Gillespie, Neil D Reeves, Joseph Pappachan, Claire O'Shea

2021-07-08

There has been a substantial amount of research involving computer methods and technology for the detection and recognition of dia..

pdCSM-cancer: Using Graph-Based Signatures to Identify Small Molecules with Anticancer Properties

Raghad Al-Jarf, Alex GC de Sa, Douglas E Pires, David B Ascher

2021-07-02

The development of new, effective, and safe drugs to treat cancer remains a challenging and time-consuming task due to limited hit..

Definition of the immune evasion-replication interface of rabies virus P protein

Jingyu Zhan, Angela R Harrison, Stephanie Portelli, Thanh Binh Nguyen, Isshu Kojima, Siqiong Zheng, Fei Yan, Tatsunori Masatani, Stephen M Rawlinson, Ashish Sethi, Naoto Ito, David B Ascher, Gregory W Moseley, Paul R Gooley

2021-07-01

Rabies virus phosphoprotein (P protein) is a multifunctional protein that plays key roles in replication as the polymerase cofacto..

The mutation G133D on Leishmania guyanensis AQP1 is highly destabilizing as revealed by molecular modeling and hypo-osmotic shock assay

Luiza G Tunes, David B Ascher, Douglas E Pires, Rubens L Monte-Neto

2021-06-29

The Leishmania aquaglyceroporin 1 (AQP1) plays an important role in osmoregulation and antimony (Sb) uptake, being determinant for..

Assessing the performance of computational predictors for estimating protein stability changes upon missense mutations

Shahid Iqbal, Fuyi Li, Tatsuya Akutsu, David B Ascher, Geoffrey Webb, Jiangning Song

2021-05-31

Understanding how a mutation might affect protein stability is of significant importance to protein engineering and for understand..

Distinguishing between PTEN clinical phenotypes through mutation analysis

Stephanie Portelli, Lucy Barr, Alex GC de Sa, Douglas E Pires, David B Ascher

2021-05-31

Phosphate and tensin homolog on chromosome ten (PTEN) germline mutations are associated with an overarching condition known as PTE..

MTR3D: identifying regions within protein tertiary structures under purifying selection

Michael Silk, Douglas E Pires, Carlos HM Rodrigues, Elston N D'Souza, Moshe Olshansky, Natalie Thorne, David B Ascher

2021-05-29

The identification of disease-causal variants is non-trivial. By mapping population variation from over 448,000 exome and genome s..

mmCSM-PPI: predicting the effects of multiple point mutations on protein-protein interactions

Carlos HM Rodrigues, Douglas E Pires, David B Ascher

2021-04-24

Protein-protein interactions play a crucial role in all cellular functions and biological processes and mutations leading to their..

SAP domain forms a flexible part of DNA aperture in Ku70/80

Ales Hnizda, Petr Tesina, Thanh-Binh Nguyen, Zdenek Kukacka, Lukas Kater, Amanda Chaplin, Roland Beckmann, David B Ascher, Petr Novak, Tom L Blundell

2021-02-16

Nonhomologous end joining (NHEJ) is a DNA repair mechanism that religates double-strand DNA breaks to maintain genomic integrity d..

Mercury methylation by metabolically versatile and cosmopolitan marine bacteria

Heyu Lin, David B Ascher, Yoochan Myung, Carl H Lamborg, Steven J Hallam, Caitlin M Gionfriddo, Kathryn E Holt, John W Moreau

2021-01-27

Microbes transform aqueous mercury (Hg) into methylmercury (MeHg), a potent neurotoxin that accumulates in terrestrial and marine ..

pdCSM-GPCR: predicting potent GPCR ligands with graph-based signatures.

João Paulo L Velloso, David B Ascher, Douglas EV Pires

2021-01-09

MOTIVATION: G protein-coupled receptors (GPCRs) can selectively bind to many types of ligands, ranging from light-sensitive compou..

ThermoMutDB: a thermodynamic database for missense mutations

Joicymara S Xavier, Nguyen Thanh-Binh, Malancha Karmarkar, Stephanie Portelli, Pamela M Rezende, Joao PL Velloso, David B Ascher, Douglas E Pires

2021-01-08

Proteins are intricate, dynamic structures, and small changes in their amino acid sequences can lead to large effects on their fol..

Unveiling six potent and highly selective antileishmanial agents via the open source compound collection 'Pathogen Box' against antimony-sensitive and -resistant Leishmania braziliensis

Juliano A Souza Silva, Luiza G Tunes, Roney S Coimbra, David B Ascher, Douglas E Pires, Rubens L Monte-Neto

2021-01-01

Despite all efforts to provide new chemical entities to tackle leishmaniases, we are still dependent on a the limited drug arsenal..

DynaMut2: Assessing changes in stability and flexibility upon single and multiple point missense mutations

Carlos HM Rodrigues, Douglas EV Pires, David B Ascher

2020-09-11

Predicting the effect of missense variations on protein stability and dynamics is important for understanding their role in diseas..

Exploring the structural distribution of genetic variation in SARS-CoV-2 with the COVID-3D online resource

Stephanie Portelli, Moshe Olshansky, Carlos HM Rodrigues, Elston N D'Souza, Yoochan Myung, Michael Silk, Azadeh Alavi, Douglas E Pires, David B Ascher

2020-09-09

mycoCSM: Using Graph-Based Signatures to Identify Safe Potent Hits against Mycobacteria

Douglas E Pires, David B Ascher

2020-07-27

Development of new potent, safe drugs to treat Mycobacteria has proven to be challenging, with limited hit rates of initial screen..

mCSM-membrane: predicting the effects of mutations on transmembrane proteins.

Douglas EV Pires, Carlos HM Rodrigues, David B Ascher

2020-07-02

Significant efforts have been invested into understanding and predicting the molecular consequences of mutations in protein coding..

mmCSM-AB: guiding rational antibody engineering through multiple point mutations

Yoochan Myung, Douglas E Pires, David B Ascher

2020-07-02

While antibodies are becoming an increasingly important therapeutic class, especially in personalized medicine, their development ..

Structure guided prediction of Pyrazinamide resistance mutations in pncA

Malancha Karmakar, Carlos HM Rodrigues, Kristy Horan, Justin T Denholm, David B Ascher

2020-02-05

Pyrazinamide plays an important role in tuberculosis treatment; however, its use is complicated by side-effects and challenges wit..

Combining structure and genomics to understand antimicrobial resistance

Tanushree Tunstall, Stephanie Portelli, Jody Phelan, Taane G Clark, David B Ascher, Nicholas Furnham

2020-01-01

Antimicrobials against bacterial, viral and parasitic pathogens have transformed human and animal health. Nevertheless, their wide..

HARP: a database of structural impacts of systematic missense mutations in drug targets of Mycobacterium leprae

Sundeep Chaitanya Vedithi, Sony Malhotra, Marcin J Skwark, Asma Munir, Marta Acebron-Garcia-De-Eulate, Vaishali P Waman, Ali Alsulami, David B Ascher, Tom L Blundell

2020-01-01

Computational Saturation Mutagenesis is an in-silico approach that employs systematic mutagenesis of each amino acid residue in th..