Miquel Duran-FrigolaIRB Barcelona Institute for Research in Biomedicine | IRB Barcelona · Group of Structural Bioinformatics and Network Biology
Miquel Duran-Frigola
Computational Drug Discovery and Bioinformatics
Ersilia Open Source Initiative
About
77
Publications
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Introduction
I am a computational biologist with a background in chemistry. My research is focused on data-driven drug discovery. I have published 22 articles in peer-reviewed journals, and I am first or corresponding author in 12 of them. Recently, I’ve led the development of the Chemical Checker, a computational platform for systems pharmacology. Now, I am willing to bring the Chemical Checker closer to the clinics, especially in neglected areas. I spend most of my free time on fiction writing.
Additional affiliations
February 2016 - July 2020
September 2011 - January 2016
January 2011 - present
Publications
Publications (77)
Diseases caused by viruses are challenging to contain, as their outbreak and spread could be very sudden, compounded by rapid mutations, making the development of drugs and vaccines a continued endeavour that requires fast discovery and preparedness. Targeting viral infections with small molecules remains one of the treatment options to reduce tran...
Chemical modulation of proteins enables a mechanistic understanding of biology and represents the foundation of most therapeutics. However, despite decades of research, 80% of the human proteome lacks functional ligands. Chemical proteomics has advanced fragment-based ligand discovery toward cellular systems, but throughput limitations have stymied...
We report the outcomes of the second session of the free online open-access workshop "Computational Applications in Secondary Metabolite Discovery (CAiSMD) Fidele Ntie-Kang and Donatus B. Eni contributed equally to this work. 2022" that took place from 09 to 11 March 2022. The first session was held from 08 to 10 March 2021 and drew the attention o...
Efficacy data from diverse chemical libraries, screened against the various stages of the malaria parasite Plasmodium falciparum, including asexual blood stage (ABS) parasites and transmissible gametocytes, serve as a valuable reservoir of information on the chemical space of compounds that are either active (or not) against the parasite. We postul...
This project is focused on nature-based discovery of antiviral agents that target putative drug targets in the human immunodeficiency virus (HIV) and the severe acute respiratory syndrome (SARS) coronavirus disease 2019 (COVID-19) virus (SARS-CoV-2) for which screening procedures have lately been established. The presenter has previously developed...
Streamlined data-driven drug discovery remains challenging, especially in resource-limited settings. We present ZairaChem, an artificial intelligence (AI)- and machine learning (ML)-based tool for quantitative structure-activity/property relationship (QSAR/QSPR) modelling. ZairaChem is fully automated, requires low computational resources and works...
[This corrects the article DOI: 10.1371/journal.pgph.0000124.].
Only around 20% of the human proteome is considered to be druggable with small-molecule antagonists. This leaves some of the most compelling therapeutic targets outside the reach of ligand discovery. The concept of targeted protein degradation (TPD) promises to overcome some of these limitations. In brief, TPD is dependent on small molecules that i...
We present ZairaChem, an artificial intelligence (AI)- and machine learning (ML)-based tool to train small-molecule activity prediction models. ZairaChem is fully automated, requires low computational resources and works across a broad spectrum of datasets, ranging from whole-cell growth inhibition assays to drug metabolism properties. The tool has...
We report the main conclusions of the first Chemoinformatics and Artificial Intelligence Colloquium, Mexico City, June 15–17, 2022. Fifteen lectures were presented during a virtual public event with speakers from industry, academia, and non-for-profit organizations. Twelve hundred and ninety students and academics from more than 60 countries. Durin...
Current antiviral drug discovery efforts face many challenges, including development of new drugs during an outbreak and coping with drug resistance due to rapidly accumulating viral mutations. Emerging artificial intelligence and machine learning (AI/ML) methods can accelerate anti-infective drug discovery and have the potential to reduce overall...
Cytokines and chemokines are immune response molecules that display diverse functions, such as inflammation and immune regulation. In Plasmodium vivax infections, the uncontrolled production of these molecules is thought to contribute to pathogenesis and has been proposed as a possible predictor for disease complications. The objective of this stud...
Background
According to the Global Strategy to Accelerate the Elimination of Cervical Cancer launched by the World Health Organizations (WHO), 70% of all women should undergo cervical cancer (CC) screening by 2030. While integrated HIV care and CC screening services exist, lack of unified data and patient management systems hinder reaching the set...
We report the main conclusions of the first Chemoinformatics and Artificial Intelligence Colloquium, Mexico City, June 15-17, 2022. Fifteen lectures were presented during a virtual public event with speakers from industry, academia, and non-for-profit organizations. Twelve hundred and ninety students and academics from more than 60 countries. Durin...
We report the main conclusions of the first Chemoinformatics and Artificial Intelligence Colloquium, Mexico City (virtual), June 15-17, 2022. Fifteen lectures were presented during a virtual and public event with speakers from industry, academia, and non-for-profit organizations. 1,290 participants, including students and academics from more than 6...
Biomedical data is accumulating at a fast pace and integrating it into a unified framework is a major challenge, so that multiple views of a given biological event can be considered simultaneously. Here we present the Bioteque, a resource of unprecedented size and scope that contains pre-calculated biomedical embeddings derived from a gigantic know...
As the response to the HIV epidemic in sub-Saharan Africa continues to mature, a growing number of people living with HIV (PLHIV) are aging and risk for non-communicable diseases increases. Routine laboratory tests of serum creatinine have been conducted to assess HIV treatment (ART) suitability. Here we utilize those measures to assess kidney func...
Through the representation of small molecule structures as numerical descriptors and the exploitation of the similarity principle, chemoinformatics has made paramount contributions to drug discovery, from unveiling mechanisms of action and repurposing approved drugs to de novo crafting of molecules with desired properties and tailored targets. Yet,...
The Columbia Cancer Target Discovery and Development (CTD2) Center is developing PANACEA, a resource comprising dose-responses and RNA sequencing (RNA-seq) profiles of 25 cell lines perturbed with ∼400 clinical oncology drugs, to study a tumor-specific drug mechanism of action. Here, this resource serves as the basis for a DREAM Challenge assessing...
Background
In spite of many years of research, our understanding of the molecular bases of Alzheimer’s disease (AD) is still incomplete, and the medical treatments available mainly target the disease symptoms and are hardly effective. Indeed, the modulation of a single target (e.g., β-secretase) has proven to be insufficient to significantly alter...
We report the major conclusions of the online open-access workshop "Computational Applications in Secondary Metabolite Discovery (CAiSMD)" that took place from 08 to 10 March 2021. Invited speakers from academia and industry and about 200 registered participants from five continents (Africa, Asia, Europe, South America, and North America) took part...
Chemical descriptors encode the physicochemical and structural properties of small molecules, and they are at the core of chemoinformatics. The broad release of bioactivity data has prompted enriched representations of compounds, reaching beyond chemical structures and capturing their known biological properties. Unfortunately, bioactivity descript...
Background
Globally, cervical cancer is the fourth leading cause of cancer-related death among women. Poor uptake of screening services contributes to the high mortality. We aimed to examine screening frequency, predictors of screening results, and patterns of sensitisation strategies by age group in a large, programmatic cohort.
Methods
We did a...
Alzheimer’s disease (AD) is the most common form of dementia. Over fifty years of intense research have revealed many key elements of the biology of this neurodegenerative disorder. However, our understanding of the molecular bases of the disease is still incomplete, and the medical treatments available for AD are mainly symptomatic and hardly effe...
The Columbia Cancer Target Discovery and Development (CTD ² ) Center has developed PANACEA (PANcancer Analysis of Chemical Entity Activity), a collection of dose-response curves and perturbational profiles for 400 clinical oncology drugs in cell lines selected to optimally represent 19 cancer subtypes. This resource, developed to study tumor-specif...
Identification of actionable genomic vulnerabilities is key to precision oncology. Utilizing a large-scale drug screening in patient-derived xenografts, we uncover driver gene alteration connections, derive driver co-occurrence (DCO) networks, and relate these to drug sensitivity. Our collection of 53 drug-response predictors attains an average bal...
Small molecules are usually compared by their chemical structure, but there is no unified analytic framework for representing and comparing their biological activity. We present the Chemical Checker (CC), which provides processed, harmonized and integrated bioactivity data on ~800,000 small molecules. The CC divides data into five levels of increas...
Chemical descriptors encode the physicochemical and structural properties of small molecules, and they are at the core of chemoinformatics. The broad release of bioactivity data has prompted enriched representations of compounds, reaching beyond chemical structures and capturing their known biological properties. Unfortunately, bioactivity descript...
Until a vaccine becomes available, the current repertoire of drugs is our only therapeutic asset to fight the SARS-CoV-2 outbreak. Indeed, emergency clinical trials have been launched to assess the effectiveness of many marketed drugs, tackling the decrease of viral load through several mechanisms. Here, we present an online resource, based on smal...
Introduction
In the current “test and treat” era, HIV programmes are increasingly focusing resources on linkage to care and same‐day antiretroviral therapy (ART) initiation to meet UNAIDS 95‐95‐95 targets. After observing sub‐optimal treatment indicators in health facilities supported by the Centre for Infectious Disease Research in Zambia (CIDRZ),...
Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks that mediate genotype–phenotype relationships1,2. Here we present a human ‘all-by-all’ reference interactome map of human binary protein interactions, or ‘HuRI’. With approximately 53,000 protein–protein interactions, HuRI...
Molecular profiling of personal cancer genomes, and the identification of actionable vulnerabilities and drug-response biomarkers, are the basis of precision oncology. Tumors often present several driver alterations that might be connected by cross-talk and feedback mechanisms, making it difficult to mark single oncogenic variations as reliable pre...
Global insights into cellular organization and function require comprehensive understanding of interactome networks. Similar to how a reference genome sequence recently revolutionized human genetics, a reference map of the human interactome network is critical to fully understand genotype-phenotype relationships. Here, we present the first human "a...
Background
The integration of large-scale drug sensitivity screens and genome-wide experiments is changing the field of pharmacogenomics, revealing molecular determinants of drug response without the need for previous knowledge about drug action. In particular, transcriptional signatures of drug sensitivity may guide drug repositioning, prioritize...
Background:
The widespread incorporation of next-generation sequencing into clinical oncology has yielded an unprecedented amount of molecular data from thousands of patients. A main current challenge is to find out reliable ways to extrapolate results from one group of patients to another and to bring rationale to individual cases in the light of...
Background
The integration of large-scale drug sensitivity screens and genome-wide experiments is changing the field of pharmacogenomics, revealing molecular determinants of drug response without the need for previous knowledge about drug action. In particular, transcriptional signatures of drug sensitivity may guide drug repositioning, prioritize...
A reverse pH gradient is a hallmark of cancer metabolism, manifested by extracellular acidosis and intracellular alkalization. While consequences of extracellular acidosis are known, the roles of intracellular alkalization are incompletely understood. By reconstructing and integrating enzymatic pH-dependent activity profiles into cell-specific geno...
Cancer cell lines (CCLs) play an important role in the initial stages of drug discovery allowing, among others, for the screening of drug candidates. As cancer cell line panels continue to grow in size and diversity, many polymorphisms in genes encoding drug-metabolizing enzymes, transporters and drug targets, as well as disease-related genes have...
In the era of systems biology, multi-target pharmacological strategies hold promise for tackling disease-related networks. In this regard, drug promiscuity may be leveraged to interfere with multiple receptors: the so-called polypharmacology of drugs can be anticipated by analyzing the similarity of binding sites across the proteome. Here, we perfo...
The massive molecular profiling of thousands of cancer patients has led to the identification of many tumor type specific driver genes. However, only a few (or none) of them are present in each individual tumor and, to enable precision oncology, we need to interpret the alterations found in a single patient. Cancer PanorOmics (http://panoromics.irb...
Approved drug molecules have undergone safety and efficacy examination, succeeding in a series of screens with typically high attrition rates. Today, these privileged entities are well characterized: the amount of data that are available for drugs —from mechanisms of action to all sorts of molecular signatures— is far beyond that of the rest of com...
While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alternatively spliced transcripts for a large number of hu...
Recent insights suggest that non-specific and/or promiscuous enzymes are common and active across life. Understanding the role of such enzymes is an important open question in biology. Here we develop a genome-wide method, PROPER, that uses a permissive PSI-BLAST approach to predict promiscuous activities of metabolic genes. Enzyme promiscuity is t...
Evolutionary conservation of the putative pdxS residues in thiG.
The residues in thiG that we predict can perform the pdxS function show a high degree of conservation, as shown in the plot. This was generated from the output of ConSurf, set with default settings except for a maximum cutoff of 70% homology in the sequences to be aligned (higher cuto...
Number of replacers per target.
(TIF)
Promiscuous functions of metabolic genes tend to be metabolic.
All target-replacer pairs predicted by our method were assessed for how often a metabolic target paired with a metabolic replacer, with a non-metabolic replacer, a non-metabolic target with a metabolic replacer, etc. We found that (A) Replacer genes with metabolic primary functions take...
Frequency of usage of Vitamin B6 as a cofactor across pathways.
(DOCX)
Inactivating the thiG proposed secondary active site removes its ability to replace pdxB, 48 hour timepoint.
Results analogous to those shown in Fig 5 of the main text are shown, but at the 48 hour timepoint (instead of 96 hours as shown in the main text). (A) Ranksum test across all IPTG concentrations in the microwell plate experiment (equivalent...
Supplementary methods and results.
(DOCX)
Statistics of gene similarity trees.
Histograms are shown of: (A) number of genes represented in each tree; (B) number of unique organisms represented in each tree; (C) number of distinct functions represented in each tree; and (D) number of E. coli metabolic functions present in each tree.
(TIF)
BLASTP Alignment of metB and metC.
(TIF)
Structural alignments of thiG and pdxS.
Multiple alignments are shown.
(TIF)
BLASTP Alignment of cysM and ilvA.
(TIF)
Sequence analysis of thiG.
(A) E. coli thiG is aligned with pdxS, the gene whose function it putatively performs promiscuously. Key residues in both genes are marked, as per the key at the bottom. Two alignments are shown as they came up in BLASTP sequence alignment. (B) The active residues of thiG for its primary function are shown, along with put...
Cancer cell lines have a prominent role in the initial stages of drug discovery, facilitating high-throughput screening of potential drugs. However, their clinical relevance remains controversial.
We assess whether drug sensitivity in cancer cell lines is able to discriminate tissue specificity. We find that cancer-specific drugs do not show higher...
We present here a new approach for the systematic identification of functionally relevant conformations in proteins. Our fully automated pipeline, based on discrete molecular dynamics enriched with coevolutionary information, is able to capture alternative conformational states in 76% of the proteins studied, providing key atomic details for unders...
Insertion of reporter cassettes into the Lgr5 locus has enabled the characterization of mouse intestinal stem cells (ISCs). However, low cell surface abundance of LGR5 protein and lack of high-affinity anti-LGR5 antibodies represent a roadblock to efficiently isolate human colonic stem cells (hCoSCs). We set out to identify stem cell markers that w...
Despite the remarkable progress achieved in the identification of specific genes involved in breast cancer (BC), our understanding of their complex functioning is still limited. In this manuscript, we systematically explore the existence of direct physical interactions between the products of BC core and associated genes. Our aim is to generate a p...
Efforts to compile the phenotypic effects of drugs and environmental chemicals offer the opportunity to adopt a chemo-centric view of human health that does not require detailed mechanistic information. Here we consider thousands of chemicals and analyse the relationship of their structures with adverse and therapeutic responses. Our study includes...
Drug side effects are one of the main health threats worldwide, and an important obstacle in drug development. Understanding how adverse reactions occur requires knowledge on drug mechanisms at the molecular level. Despite recent advances, the need for tools and methods that facilitate side effect anticipation still remains. Here, we present IntSid...
Despite significant advances in the identification of specific genes and pathways important in the onset and progression of colorectal cancer (CRC), mechanistic insight into the relationship between driver and susceptibility genes is needed. In this manuscript, we systematically explore physical interactions between causative and putative CRC susce...