Marta Filizola

Marta Filizola
Icahn School of Medicine at Mount Sinai | MSSM · Pharmacological Sciences

BSc, MS, PhD

About

275
Publications
22,653
Reads
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6,879
Citations
Citations since 2017
66 Research Items
3239 Citations
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20172018201920202021202220230100200300400500
20172018201920202021202220230100200300400500
20172018201920202021202220230100200300400500
Introduction
The Filizola Laboratory (www.filizolalab.org) uses a variety of computational structural biology tools, ranging from molecular modeling, bioinformatics, chemoinformatics, molecular dynamics simulations (both standard and enhanced), and rational drug design approaches, to achieve a detailed mechanistic understanding of signal transduction processes triggered by molecular recognition in membrane protein complex systems such as G Protein-Coupled Receptors (GPCRs) and beta3 integrins.
Additional affiliations
March 2015 - present
Icahn School of Medicine at Mount Sinai
Position
  • co-Director Ph.D. Program
Description
  • Dr. Filizola is co-Director of the Biophysics and Systems Pharmacology (BSP) training area of the Graduate School of Mount Sinai. She participates as teaching faculty in BSP and the Design, Technology, and Entrepreneurship (DTE) training area.
July 2014 - February 2016
Icahn School of Medicine at Mount Sinai
Position
  • Professor (Full)
September 2012 - February 2015
Icahn School of Medicine at Mount Sinai
Position
  • co-Director Ph.D. Program
Description
  • Dr. Filizola is co-Director of the Structural/Chemical Biology and Molecular Design (SMD) training area of the Graduate School of Mount Sinai. She participates as teaching faculty in SMD and Systems Biology of Disease and Therapeutics (SBDT).
Education
October 1994 - January 1999
II Universita' degli Studi di Napoli
Field of study
  • Computational Chemistry
October 1992 - October 1993
Università degli Studi di Napoli 'Federico II'
Field of study
  • Chemistry
October 1988 - October 1993
University of Naples Federico II
Field of study
  • Chemistry

Publications

Publications (275)
Article
Full-text available
While the therapeutic effect of opioids analgesics is mainly attributed to µ-opioid receptor (MOR) activation leading to G protein signaling, their side effects have mostly been linked to β-arrestin signaling. To shed light on the dynamic and kinetic elements underlying MOR functional selectivity, we carried out close to half millisecond high-throu...
Article
Full-text available
The lipid composition of cell membranes has increasingly been recognized as playing an important role in the function of various membrane proteins, including G Protein-Coupled Receptors (GPCRs). For instance, experimental and computational evidence has pointed to lipids influencing receptor oligomerization directly, by physically interacting with t...
Article
Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective µ-opioid receptor (MOR) agoni...
Article
Substantial attention has recently been devoted to G protein-biased agonism of the µ-opioid receptor (MOR) as an ideal new mechanism for the design of analgesics devoid of serious side effects. However, designing opioids with appropriate efficacy and bias is challenging because it requires an understanding of the ligand binding process and of the a...
Article
Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of...
Article
Full-text available
G Protein-Coupled Receptors (GPCRs) are a large family of membrane proteins with pluridimensional signaling profiles. They undergo ligand-specific conformational changes, which in turn lead to the differential activation of intracellular signaling proteins and the consequent triggering of a variety of biological responses. This conformational plast...
Article
Inhibitors of integrin αVβ3 have therapeutic promise for a variety of diseases. Most αVβ3-targeting small molecules patterned after the RGD motif are partial agonists because they induce a high-affinity, ligand-binding conformation and prime the receptor to bind the ligand without an activating stimulus, in part via a charge-charge interaction betw...
Preprint
Full-text available
G proteins are major signaling partners for G protein-coupled receptors (GPCRs). Although stepwise structural changes during GPCR–G protein complex formation and guanosine diphosphate (GDP) release have been reported, no information is available with regard to guanosine triphosphate (GTP) binding. Here, we used a novel Bayesian integrative modeling...
Article
Full-text available
Mitragynine and 7-hydroxymitragynine (7OH) are the major alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure–activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and arrestin signali...
Article
Purpose: Mantle Cell Lymphoma (MCL) is a fatal subtype of Non-Hodgkin's Lymphoma. SOX11 transcription factor is overexpressed in the majority of nodal MCL. We have previously reported that B-cell specific overexpression of SOX11 promotes MCL pathogenesis via critically increasing BCR signaling in vivo. SOX11 is an attractive target for MCL therapy...
Article
Positive allosteric modulators (PAMs) of the μ-opioid receptor (MOR) have been proposed to exhibit therapeutic potential by maximizing the analgesic properties of clinically used opioid drugs while limiting their adverse effects or risk of overdose as a result of using lower drug doses. We herein report in vitro and in vivo characterization of two...
Preprint
Full-text available
Positive allosteric modulators (PAMs) of the μ-opioid receptor (MOR) have been proposed to exhibit therapeutic potential by maximizing the analgesic properties of clinically used opioid drugs while limiting their adverse effects or risk of overdose as a result of using lower drug doses. We herein report in vitro and in vivo characterization of two...
Preprint
Full-text available
Dried kratom leaves are anecdotally used for the treatment of pain, opioid dependence, and alcohol use disorder. We have previously shown that kratom and its natural products (mitragynine) and semi-synthetic analogs (7-hydroxy mitragynine (7OH) and mitragynine pseudoindoxyl) are mu opioid receptor (MOR) agonists that show minimal beta-arrestin2 rec...
Article
Full-text available
The metabotropic glutamate receptors (mGluRs) form a family of neuromodulatory G protein-coupled receptors that contain both a seven-helix transmembrane domain (TMD) and a large extracellular ligand-binding domain (LBD) which enables stable dimerization. While numerous studies have revealed variability across subtypes in the initial activation step...
Article
The murine monoclonal antibody (mAb) PT25-2 induces αIIbβ3 to bind ligand and initiate platelet aggregation. The underlying mechanism is unclear, because previous mutagenesis studies suggested that PT25-2 binds to the αIIb β propeller, a site distant from the Arg-Gly-Asp–binding pocket. To elucidate the mechanism, we studied the αIIbβ3–PT25-2 Fab c...
Preprint
Full-text available
The metabotropic glutamate receptors (mGluRs) form a family of neuromodulatory G protein-coupled receptors that contain both a seven-helix transmembrane domain (TMD) and a large extracellular ligand-binding domain (LBD) which enables stable dimerization. While numerous studies have revealed variability across subtypes in the initial activation step...
Article
Pain management devoid of serious opioid adverse effects is still far from reach despite vigorous research and development efforts. Alternatives to classical opioids have been sought for years, and mounting reports of individuals finding pain relief with kratom have recently intensified research on this natural product. Although the composition of...
Article
Full-text available
Serotonin receptors (5-HT 3A R) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just...
Article
Full-text available
Determining the drug-target residence time (RT) is of major interest in drug discovery given that this kinetic parameter often represents a better indicator of in vivo drug efficacy than binding affinity. However, obtaining drug-target unbinding rates poses significant challenges, both computationally and experimentally. This is particularly palpab...
Article
Full-text available
G-protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new three-dimensional (3D) molecular structures of GPCRs (3D-GPCRome) over the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this...
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Methadone is a synthetic opioid agonist with notoriously unique properties, such as lower abuse liability and induced relief of withdrawal symptoms and drug cravings, despite acting on the same opioid receptors triggered by classical opioids, in particular the µ-opioid receptor (MOR). Its distinct pharmacologic properties, which have recently been...
Preprint
Full-text available
Serotonin receptors (5-HT 3A R) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just...
Article
Objective The αIIbβ3 antagonist antiplatelet drug abciximab is the chimeric antigen-binding fragment comprising the variable regions of murine monoclonal antibody 7E3 and the constant domains of human IgG1 and light chain κ. Previous mutagenesis studies suggested that abciximab binds to the β3 C177-C184 specificity-determining loop (SDL) and Trp129...
Article
DN, YZ, AS, & JL contributed equally, as did MF, TW, & BSC The αIIbβ3 antagonist antiplatelet drug abciximab, approved in 1994, is the chimeric antigen-binding fragment (Fab) comprising the variable regions of murine mAb 7E3 and human IgG1 and light chain κ constant domains. In studies involving thousands of patients undergoing percutaneous coronar...
Article
Full-text available
Transient receptor potential vanilloid 5 (TRPV5) is a highly calcium selective ion channel that acts as the rate-limiting step of calcium reabsorption in the kidney. The lack of potent, specific modulators of TRPV5 has limited the ability to probe the contribution of TRPV5 in disease phenotypes such as hypercalcemia and nephrolithiasis. Here, we pe...
Article
In the era of opioid abuse epidemics, there is an increased demand for understanding how opioid receptors can be allosterically modulated to guide the development of more effective and safer opioid therapies. Among the modulators of the μ-opioid (MOP) receptor, which is the pharmacological target for the majority of clinically used opioid drugs, ar...
Article
Full-text available
Effective treatments for pain management remain elusive due to the dangerous side-effects of current gold-standard opioid analgesics, including the respiratory depression that has led to skyrocketing death rates from opioid overdoses over the past decade. In an attempt to address the horrific opioid crisis worldwide, the National Institute on Drug...
Article
Full-text available
The integrin αVβ3 receptor has been implicated in several important diseases, but no αVβ3 antagonists are approved for human therapy. One possible limitation of current small-molecule antagonists is their ability to induce a major conformational change in the receptor that induces it to adopt a high-affinity ligand-binding state. In response, we us...
Article
The PLUMED consortium unifies developers and contributors to PLUMED, an open-source library for enhanced- sampling, free-energy calculations and the analysis of molecular dynamics simulations. Here, we outline our efforts to promote transparency and reproducibility by disseminating protocols for enhanced-sampling molecular simulations.
Article
Full-text available
Serotonin receptor (5-HT3AR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of competitive antagonists, cause functional inhibition of 5-HT3AR in the gastrointestinal tract and brainstem, acting as effective anti-emetic agents. Despit...
Preprint
In the era of opioid abuse epidemics, there is an increased demand for understanding how opioid receptors can be allosterically modulated to guide the development of more effective and safer opioid therapies. Among the modulators of the µ-opioid (MOP) receptor, which is the pharmacological target for the majority of clinically used opioid drugs, ar...
Preprint
Full-text available
The integrin αVβ3 receptor has been implicated in several important diseases, but no αVβ3 antagonists are approved for human therapy. One possible limitation of current small-molecule antagonists is their ability to induce a major conformational change in the receptor that induces it to adopt a high-affinity ligand-binding state. In response, we us...
Article
G-protein-coupled receptors (GPCRs)are allosteric signaling machines that trigger distinct functional responses depending on the particular conformational state they adopt upon binding. This so-called GPCR functional selectivity is prompted by ligands of different efficacy binding at orthosteric or allosteric sites on the receptor, as well as by in...
Article
Full-text available
The differential modulation of agonist and antagonist binding to opioid receptors (ORs) by sodium (Na⁺) has been known for decades. To shed light on the molecular determinants, thermodynamics, and kinetics of Na⁺ translocation through the μ-OR (MOR), we used a multi-ensemble Markov model framework combining equilibrium and non-equilibrium atomistic...
Data
List of mouse MOR residues selected for tICA analysis. (DOCX)
Data
List of MOR residue pairs whose minimum heavy atom distance fluctuation has a correlation larger than 0.6 to the most dominant tICA0 and tICA1 components in the simulated active or inactive MOR systems. (DOCX)
Data
Transition times (in μs) between metastable states obtained from the MSM constructed for the simulated active MOR system with a protonated D2.50. The label “Inf” indicates the absence of transitions between two states. (DOCX)
Data
Spatial location of the 105 residues listed in S1 Table in a representative active MOR state from molecular dynamics simulations shown in vertical and horizontal views. The Cα atoms of these residues are shown as spheres. (TIFF)
Data
Summary of number, type, and length of simulations. (DOCX)
Data
Transition times (in μs) between metastable states obtained from the MSM constructed for the simulated inactive MOR system. The label “Inf” indicates the absence of transitions between two states. (DOCX)
Data
Transition times (in μs) between metastable states obtained from the MSM constructed for the simulated active MOR system with a charged D2.50. The label “Inf” indicates the absence of transitions between two states. (DOCX)
Data
The MSM implied time scales as a function of lag-time for the first 10 eigenvalues obtained for each simulated MOR system. The data points correspond to the median estimated from all bootstraps samples and the full sample. The upper and lower error bars represent the differences between the median and 1st and 3rd quantiles, respectively. (TIFF)
Data
Saturation of 3H-DAMGO binding in the absence and presence of NaCl. Binding of 3H-DAMGO was carried out with for increasing ligand concentrations in the absence (red) and presence (blue) of NaCl (25 nM). Results are the means ± s.e.m. of three independent replications. Nonlinear regression analysis of the curves is indicated by the solid lines. KD...
Data
Graphical illustration of MOR residue pairs whose minimum heavy atom distance fluctuations have a correlation larger than 0.6 to the most dominant tIC0 and tIC1 components. (TIFF)
Data
Fraction of Na+-bound receptor as a function of the extracellular sodium concentration for the inactive MOR (green), active MOR with charged D1142.50 (red), active MOR with protonated D1142.50 (brown), and active MOR at constant pH = 7 (orange). A dashed black line indicates 50% occupation probability that intersects the curves at the corresponding...
Article
Full-text available
Computational strategies aimed at unveiling the thermodynamic and kinetic properties of G Protein-Coupled Receptor (GPCR) activation require extensive molecular dynamics simulations of the receptor embedded in an explicit lipid-water environment. A possible method for efficiently sampling the conformational space of such a complex system is metadyn...
Article
G-protein-coupled receptors (GPCRs) control vital cellular signaling pathways. GPCR oligomerization is proposed to increase signaling diversity. However, many reports have arrived at disparate conclusions regarding the existence, stability, and stoichiometry of GPCR oligomers, partly because of cellular complexity and ensemble averaging of intrarec...
Preprint
Computational strategies aimed at unveiling the thermodynamic and kinetic properties of G Protein-Coupled Receptor (GPCR) activation require extensive molecular dynamics simulations of the receptor embedded in an explicit lipid-water environment. A possible method for efficiently sampling the conformational space of such a complex system is metadyn...
Article
Full-text available
Various experimental and computational techniques have been employed over the past decade to provide structural and thermodynamic insights into G Protein-Coupled Receptor (GPCR) dimerization. Here, we use multiple microsecond-long, coarse-grained, biased and unbiased molecular dynamics simulations (a total of ~4 milliseconds) combined with multi-en...
Article
Having accidental deaths from opioid overdoses almost quadrupled over the past fifteen years, there is a strong need to develop new, non-addictive medications for chronic pain to stop one of the deadliest epidemics in American history. Given their potentially fewer on-target overdosing risks and other adverse effects compared to classical opioid dr...
Chapter
Full-text available
An increasing number of G protein-coupled receptor (GPCR) crystal structures provide important—albeit static—pictures of how small molecules or peptides interact with their receptors. These high-resolution structures represent a tremendous opportunity to apply molecular dynamics (MD) simulations to capture atomic-level dynamical information that is...
Article
Full-text available
The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca2+, that is present primarily at the apical membrane of distal tubule epithelial cells in the kidney and plays a key role in Ca2+ reabsorption. Here we present the structure of the full-l...
Article
Full-text available
Gαs (Gs) and Gαolf (Golf) are highly homologous G protein α; subunits that activate adenylate cyclase, thereby serving as crucial mediators of intracellular signaling. Owing to their dramatically different brain expression patterns, we studied similarities and differences between their activation processes with the aim of comparing their receptor c...
Article
The opioid receptors are key targets in the treatment of acute and chronic pain, and the development of novel analgesics with reduced side effects is crucial in the search for more effective medications. The crystal structures of opioid receptors have provided a wealth of knowledge on many aspects of opioid receptor pharmacology and function, inclu...
Article
Full-text available
Key Points Activation of αIIbβ3 is required for its ancillary site interactions with fibrinogen fragment D lacking the γ-chain dodecapeptide (‘D98’). EDTA can paradoxically induce normal αIIbβ3 to interact with fibrinogen fragment ‘D98.’
Data
Lipid distributions of A) PA, B) PI, C) PIP1-3, D) PS, and E) GM around individual protomers during the final 2 μs of the low receptor density simulations with the BB beads of the receptors fixed. The dots indicate the centers of mass of the BB beads of the receptor helices. (PDF)
Data
Plots showing the average lipid order (left) and bilayer thickness (right) for one high receptor density simulation run of a mixed array of inactive and active MOR during which time the BB beads of the receptors were fixed. The data is averaged over all lipids, excluding the ones that flip-flop across the membrane (i.e. CHOL, CER, and DAG). For the...
Data
Structure of A) a cholesterol, B) a PC/SM lipid, and C) a GM lipid with the ROH, GL1, and AM1 beads used in the lipid analysis colored in cyan. The headgroup beads are in pink and the remaining tail beads in grey. (PDF)
Data
The fraction of lipids with each headgroup in the plasma membrane at the start of all of the simulations. ‘Other’ in the upper leaflet includes: CER (0.7%), LPC (1.0%), and DAG (0.4%). ‘Other’ in the lower leaflet includes: PA (1.5%), PIP1-3 (1.6%), CER (0.1%), and DAG (0.5%). The total number of lipids in the upper and lower leaflets was approxima...
Data
The bilayer thickness (nm, top row) and lipid order (bottom row) of the non-flipping lipids within 3.125 nm of the protein center of mass calculated as a function of the helix index during the last 2 μs of membrane equilibration of the high receptor density simulations with the BB beads of the receptors kept fixed. For the thickness, the average an...
Data
The residues on helices involved in dimer interfaces with which CHOL is in contact for more than 50% of the final microsecond of the high receptor density simulations with the receptors free to move. Residues in contact with CHOL for more than 75% of the simulation time are in bold. (PDF)
Data
Plots showing the average lipid order (left column) and bilayer thickness (nm, right column) during the final 2 μs of membrane equilibration for one high receptor density simulation run of inactive (top row) or active (bottom row) receptors with fixed BB beads. The data is averaged over all lipids, excluding the ones that flip-flop across the membr...
Data
The correlation between the bilayer thickness and the lipid order for the high receptor density simulations of inactive (left) or activated (right) MOR with the BB beads of the receptors fixed. For each bin, the average order is plotted vs. the average thickness. (PDF)
Data
Tilting of the principal axis of the active or inactive MOR in the low receptor density simulations with either restrained BB beads or freely moving receptors. The angle θ (radial coordinate, measuring the amount of tilting) is the angle between the protein principal axis and the normal to the membrane, while φ (polar angle, representing the direct...