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Simon Cocklin

Simon Cocklin, PhD

Associate Professor

Department: Biochemistry & Molecular Biology


  • PhD, Molecular Genetics - University of Newcastle (2001)

Simon Cocklin is an associate professor in the Department of Biochemistry & Molecular Biology at Drexel University College of Medicine.

Research Interests

Macromolecular interaction analysis, HIV-1 replication, strucuture-function relationships, ligand-receptor interactions


HIV-1 is a small virus that expresses only 16 proteins. In order for HIV-1 to replicate and cause disease, its proteins must interact with and usurp the normal functions of host cell proteins. This interplay between viral and host proteins is evident at virtually every step in the HIV replication cycle, from binding and entry to particle release.

Research in my laboratory is focused upon two main areas of HIV-1 research: small-molecule inhibitor discovery and the identification and investigation of host cell proteins that critically interact with the HIV-1 Gag protein. We have adopted a multidisciplinary approach to researching these areas, combining data from computational, biochemical, biophysical, virological, and structural investigations to achieve our goals. We actively collaborate with other research groups within Drexel University College of Medicine, and at Howard Hughes Medical Institute at the University of Maryland, University of Pennsylvania, Johns Hopkins University, Dana Farber Cancer Institute (Harvard University) and the Southern Research Institute.

Current Major Projects

Cellular biology and host cell protein interactions of the HIV-1 MA protein

The Gag polyprotein is a structural protein that plays a central role in the late stages of viral replication. The Gag polyprotein consists of several domains, three of which are functionally conserved among retroviruses: the nucleocapsid (NC) domain; the capsid (CA) domain; and the myristoylated matrix (MA) domain. The HIV-1 MA protein, encoded as the N-terminal portion of Gag, is a small, multifunctional protein responsible for regulating various stages of the viral replication cycle. Functional studies have revealed that the matrix protein (MA) of HIV-1 is critically involved in key processes including the intracellular localization of the Gag polyprotein, the incorporation of the viral envelope glycoprotein into virus particles, and early post-entry events. Moreover, several lines of research indicate these roles may be dependent upon MA interacting with host proteins, yet relatively little is known about the identity or role of these cellular co-factors. Several studies have either directly or indirectly demonstrated the interaction of MA with a number of cellular factors. These include the minor phospholipid, phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2], AP-2, and AP-3 clathrin adaptor complexes; HO3, a histidyl-tRNA synthetase, the translation elongation factor 1-α; the polycomb group protein embryonic ectoderm development (EED); the suppressor of cytokine signaling 1 (SOCS1) protein; calmodulin (CaM); and the adenosine diphosphate ribosylation factor (Arf) proteins.

Given the breadth of functions of the HIV-1 MA protein in both the early and late stages of the viral life cycle, we believe that MA may participate in a larger number of interactions with host cell factors than previously appreciated and that each interaction may itself modulate the interactions that the HIV-1 MA protein is capable of by alteration of the structure of the protein. We have recently performed an exhaustive yeast two-hybrid (Y2H) screen, using HIV-1 MA as bait, and against a cDNA library from primary human leukocytes and activated mononuclear cells. This screen has resulted in the identification of a number of novel host cell protein interactors, in addition to the discovery of proteins previously demonstrated to be required for HIV-1 replication. Interestingly, a common theme among the hits is the participation in intracellular protein transport processes. We are currently confirming and investigating these hits with a view to an improved understanding of the role of the HIV-1 MA protein within the HIV-1 replication cycle and the possibility of identifying new critical interactions that may be targeted therapeutically.

Field point representation of first generation CA inhibitor compound, I-XW-053

Figure 1. Field point representation of first generation CA inhibitor compound, I-XW-053, generated using FieldTemplater (Cresset BioMolecular Discovery, Welwyn Garden City, Hertfordshire, UK; Blue field points (spheres) highlight energy minima for a positively charged probe, red for a negative probe. Yellow spheres represent an attractive van der Waals minima for a neutral probe and orange spheres represent hydrophobic centroids. Oxygen atoms are shown in red, nitrogen in blue. The size of the points is related to the strength of the interaction.

Small-molecule inhibitor discovery

Combination anti-HIV therapy, commonly referred to as highly active antiretroviral therapy, has led to a dramatic reduction in mortality and morbidity in HIV-infected patients. Currently more than 25 antiretroviral drugs are available to treat HIV infection. The majority of them target the HIV-1 reverse transcriptase (RT) and protease enzymes. Recently, antiretroviral drugs that inhibit the viral integrase, the six-helix bundle core formation of the gp41 transmembrane protein, or the host cell protein CCR5 required for virus-cell fusion have been approved for the clinic. Despite these successes, current therapies for HIV-1 are limited by the development of multidrug-resistant virus and by significant cumulative drug toxicities. The development of new classes of antiretroviral agents with novel modes of action is therefore highly desirable and is a driving force for the pursuit of small-molecule inhibitors of other, more difficult viral targets, such as the viral regulatory and accessory proteins. We are currently exploring small-molecule targeting of the HIV-1 Gag (matrix and capsid domains) and the HIV-1 Env complex as an antiviral strategy.

Small-molecule modulation of the HIV-1 capsid (CA) protein

The HIV-1 capsid (CA) is an essential viral protein that performs two major roles in the life cycle of HIV-1: one structural, in which it forms a protein shell that shields both the viral genome and the replicative enzymes of HIV-1, and the other regulatory, in which the precise temporal disassembly of this shell coordinates post-entry events such as reverse transcription. The CA protein is composed of two domains: the C-terminal domain (CTD) and the N-terminal domain (NTD). Both of these domains make critical inter- and intra-domain interactions that are critical for the formation of the capsid shell. The NTD of the capsid protein is the structural anchor for the formation of the hexameric lattice by which the HIV-1 capsid assembles. The stability of this hexameric lattice, which is also conferred by the NTD, regulates the precise temporal series of replicative events after fusion; capsids that are too stable or too unstable do not enter into reverse transcription correctly. Therefore, in theory, any compound that disrupts the normal interactions of the capsid—whether by inhibiting assembly, accelerating disassembly, or artificially stabilizing the core—should attenuate the virus. The essential roles played by capsid within the HIV-1 life cycle, coupled with the existence of known compounds with the ability to disrupt CA-CA interactions, make the capsid's hexamerization interface a new, attractive therapeutic target. As such, we have employed a virtual screening strategy to identify small molecules with the potential to alter assembly of HIV-1 CA by perturbation of the N-terminal domain (NTD-NTD) hexamerization interface. This strategy has resulted in the identification of a number of compounds, which after size reduction and optimization of their physical-chemical properties, inhibited the replication of a diverse panel of primary HIV-1 isolates in peripheral blood mononuclear cells (PBMCs), while displaying no appreciable cytotoxicity. This antiviral activity was restricted to HIV-1 as determined by cytopathic effect assays against a panel of DNA- and RNA-based viruses. The direct interaction of the compounds with the HIV-1 CA protein has been quantified using surface plasmon resonance (SPR) and isothermal titration calorimetry. Moreover, SPR studies using CA proteins mutated in the compounds' proposed binding region confirm that residues involved in the NTD-NTD interface are required for interaction. We are currently applying medicinal chemistry approaches to improve the efficacy of these compounds.

Surface rendering of HIV-1 MA

Figure 2. Surface rendering of HIV-1 MA showing the residues that form the collective compound binding site, along with the docked structures of selected compound hits.

Targeting the HIV-1 matrix (MA) protein phosphoinositide [4,5] bisphosphate (PIP2)-binding site

The HIV-1 matrix (MA) protein is a structural protein critically involved in both pre- and post-integration stages in the life cycle of the retrovirus. The HIV-1 MA protein has long been known to be crucial for virion assembly, functioning to target assembly to the plasma membrane and facilitating the incorporation of the envelope glycoproteins, gp120 and gp41, into nascent virions. The details regarding its precise function in the early stages of HIV-1 replication are less well defined.

Binding of MA to phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] and the conformational changes that this interaction elicits are key steps in the replication of HIV-1. The high degree of conservation of this region, coupled with its modulatory effect on the structure of the MA protein, makes the MA PI(4,5)P2-binding site a potentially attractive antiviral target. As such, we initiated a structure-based in silico screen to identify novel small molecules with the potential to bind to HIV-1 MA within this region. This approach yielded the identification of four compounds that bind to the HIV-1 MA protein (as judged by surface plasmon resonance) and inhibit the replication of primary HIV-1 isolates in PBMCs with half-maximal inhibitory concentration (IC50) values of 9 to 30 µM. These compounds display specificity to retroviruses, inhibiting HIV-1 and simian immunodeficiency virus (SIV), while showing no effect on other DNA- and RNA-based viruses and little or no cytotoxicity up to 100 µM. Moreover, these four compounds can be grouped into three classes: early-stage inhibitors, late-stage inhibitors, and one compound that appears to disrupt both early and late events. With these exciting results now in hand, we are further investigating their precise mode of action and applying medicinal chemistry approaches to improve the efficacy of these compounds.

Small-molecule inhibition of HIV-1 entry into host cells

The entry of HIV-1 into permissible cells is a complex series of events, orchestrated by the viral envelope glycoprotein complex, the only viral components exposed on the virion surface. As the only viral products accessible to the host cell immune system, the Env glycoproteins, gp120 and gp41, have evolved several strategies to mask functionally important regions from the neutralizing antibody response. These include the presence of surface-exposed variable loops on gp120, a high degree of glycosylation, the lability and defectiveness of many envelope glycoprotein spikes (possible immunologic decoys), and conformational flexibility. The Env complex is organized on the virion surface as trimeric spikes, composed of three gp120 molecules noncovalently linked to three gp41 molecules. The heavily glycosylated surface gp120 contains a core composed of conserved regions (C1 to C5) and hypervariable regions that are mostly disulfide-constrained, surface-exposed loop structures (V1 to V5) that retain a large degree of flexibility. The transmembrane glycoprotein gp41 contains the fusion peptide, which is inserted into the membrane of the target cells, as well as two heptad repeat (HR) domains (aminoterminal or HR1 and carboxyterminal or HR2) that are implicated in the formation of a six-helix-bundle fusion intermediate through a conformational change following receptor interaction. HIV-1 infection usually occurs only after two sequential and specific binding steps: first, to the CD4 antigen present in CD4+ T cells, monocyte/macrophages, and other immune and nonimmune cells; and second, to a member of the chemokine receptor subfamily, within the large G protein–coupled family of receptors, mainly CCR5 and/or CXCR4.

In the HIV-1 entry field, two main gp120-targeted inhibitor chemotypes predominate: the NBD-556 analogues and the BMS-377806 analogues. NBD-556 and its analogues bind to the conserved CD4-binding site in gp120 and block the interaction of the Env compex with cellular CD4. The binding site for BMS-377806 and its analogues is poorly understood and based on resistance mutation data may be a composite site composed of regions of gp120 and g41. The mechanism of action of BMS-377806 and its derivatives is under debate too, with some studies claiming a CD4 binding inhibition mechanism and others describing an allosteric mechanism which prevents the propagation of the receptor binding signals from gp120 to gp41. Given the huge therapeutic potential of inhibiting HIV-1 entry, the development of new chemotypes that target viral entry with broad activities is highly desirable. We are currently using a combination high content pharmacophore virtual screening and scaffold-hopping via bioisosteric replacement to identify novel chemotypes in this inhibitor class.

In the Media


“Field-based potency optimization of a novel azabicyclo-hexane scaffold HIV-1 entry inhibitor”
Meuser ME,  Rashad AA, Ozorowski G, Dick A, Ward AB, and Cocklin S
, Under revision, 2019

"Kinetic Characterization of Novel HIV-1 Entry Inhibitors: Discovery of a Relationship between Off-Rate and Potency"
Meuser ME, Murphy MB, Rashad AA, and Cocklin S
Molecules, 23(8), 1940, 2018

"Exploring Modifications of an HIV-1 Capsid Inhibitor: Design, Synthesis, and Mechanism of Action"
Xu JP, Francis AC, Meuser ME, Mankowski M, Ptak RG, Rashad AA, Melikyan GB, and Cocklin S
Journal of Drug Design and Research, 5(2):1070, 2018

"Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library"
Wu G, Zalloum WA, Meuser ME, Jing L, Kang D, Chen CH, Tian Y, Zhang F, Cocklin S,* Lee KH,* Liu X,* and Zhan P*
European Journal of Medicinal Chemistry, 5;158:478-492, 2018
*Corresponding authors

"Interaction between the AAA+ ATPase p97 and its cofactor ataxin3 in health and disease: Nucleotide-induced conformational changes regulate cofactor binding"
Rao MV, Williams DR, Cocklin S, and Loll PJ
Journal of Biological Chemistry, 292(45):18392-18407, 2017

"The spliceosomal proteins PPIH and PRPF4 exhibit bi-partite binding"
Rajiv C, Jackson SR, Cocklin S, Eisenmesser EZ, Davis TL
Biochemical Journal, 474(21):3689-3704, 2017

"IgG Binding Characteristics of Rhesus Macaque FcγR"
Chan YN, Boesch AW, Osei-Owusu NY, Emileh A, Crowley AR, Cocklin SL, Finstad SL, Linde CH, Howell RA, Zentner I, Cocklin S, Miles AR, Eckman GW, Alter G, Schmitz JE, and Ackerman ME
Journal of Immunology, 197(7):2936-47, 2016

"Phosphorylation of the RNA-binding protein Dazl by MAPKAP kinase 2 regulates spermatogenesis"
Williams PA, Krug MS, McMillan EA, Peake JD, Davis TL, Cocklin S, and Strochlic TI
Molecular Biology of the Cell, 27(15):2341-50, 2016

"Insertion of perilipin 3 into glycero(phosphor-)lipid monolayer depend on lipid headgroup and acylchain species"
Mirheydari M, Rathnayake SS, Frederick H, Arhar T, Mann EK, Cocklin S, and Kooijman EE
Journal of Lipid Research, 57(8):1465-76, 2016

"Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors"
Huang F, Goyal N, Sullivan K, Hanamshet K, Patel M, Mazina OM, An WF, Spoonamore J, Metkar S, Emmitte KA, Cocklin S, Skorski T, and Mazin AV
Nucleic Acid Research, 44(9):4189-99, May 19, 2016

"Identification of a small molecule HIV-1 inhibitor that targets the hexameric capsid"
Xu JP, Branson JD, Lawrence R, and Cocklin S
Bioorganic and Medicinal Chemistry Letters, 26(3):824-8, Feb 1, 2016

"Core chemotype diversification in the HIV-1 entry inhibitor class using field-based bioisosteric replacement"
Tuyishime M, Lawrence R, and Cocklin S
Bioorganic and Medicinal Chemistry Letters, 26(1):228-34, Jan 1, 2016

"Discovery and optimization of novel small-molecule HIV-1 entry inhibitors using field-based virtual screening and bioisosteric replacements"
Tuyishime M, Danish M, Princiotto A, Mankowski MK, Lawrence R, Lombart HG, Esikov K, Berniac J, Liang K, Ji J, Ptak RG, Madani N, and Cocklin S
Bioorganic and Medicinal Chemistry Letters, 24(23):5439-5445, Oct 16, 2014

"Structure-activity relationships of a novel capsid targeted inhibitor of HIV-1 replication"
Kortagere S,* Xu JP, Mankowski M, Ptak RG, and Cocklin S*
Journal of Chemical Information and Modeling, 54(11):3080-90, Nov 24, 2014
*Corresponding authors

"An Optimized, Synthetic DNA Vaccine Encoding the Toxin A and Toxin B Receptor Binding Domains of Clostridium difficile Induces Protective Antibody Responses In Vivo"
Baliban SM, Michael A, Shammassian B, Mudakha S, Khan AS, Cocklin S, Zentner I, Latimer BP, Bouillaut L, Hunter M, Marx P, Sardesai NY, Welles SL, Jacobson JM, Weiner DB, and MA Kutzler
Infection and Immunity, 82(10):4080-91, 2014

"The high resolution structure of tyrocidine A reveals an amphipathic dimer"
Loll PJ, EC Upton, V Nahoum, NJ Economou, and S Cocklin
Biochimica et Biophysica Acta, 1838:1199-1207, 2014

"Identification of a Small-Molecule Inhibitor of HIV-1 Assembly that Targets the Phosphatidylinositol (4,5)-bisphosphate Binding Site of the HIV-1 Matrix Protein"
Zentner I, Sierra LJ, Fraser AK, Maciunas L, Mankowski MK, Vinnik A, Fedichev P, Ptak RG, Martin-Garcia J, and Cocklin S
ChemMedChem 8:426-432, 2013

"Reevaluation of the Requirement for TIP47 in Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Incorporation"
Checkley MA, Luttge BG, Mercredi PY, Kyere SK, Donlan J, Murakami T, Summers MF, Cocklin S, and EO Freed
J Virol 87:3561-3570, 2013

"Discovery of a small-molecule antiviral targeting the HIV-1 matrix protein"
Zentner I, Sierra LJ, Maciunas L, Vinnik A, Fedichev P, Mankowski MK, Ptak RG, Martin-Garcia J, and Cocklin S
Bioorganic & Medicinal Chemistry Letters 23:1132-1135, 2013

"Inhibiting early-stage events in HIV-1 replication by small-molecule targeting of the HIV-1 capsid"
Kortagere S, Madani N, Mankowski MK, Schon A, Zentner I, Swaminathan G, Princiotto A, Anthony K, Oza A, Sierra LJ, Passic SR, Wang X, Jones DM, Stavale E, Krebs FC, Martin-Garcia J, Freire E, Ptak RG, Sodroski J, Cocklin S, and Smith AB, 3rd. 
Journal of Virology 86:8472-8481, 2012

"Solution structure studies of monomeric human TIP47/perilipin-3 reveal a highly extended conformation"
Hynson RM, Jeffries CM, Trewhella J, and Cocklin S
Proteins 80:2046-2055, 2012

"Inhibition of homologous recombination in human cells by targeting RAD51 recombinase"
Huang F, Mazin OM, Zentner IJ, Cocklin S and Mazin AV
Journal of Medicinal Chemistry 55:3011-3020, 2012

"A carrier protein strategy yields the structure of dalbavancin"
Economou NJ, Nahoum V, Weeks SD, Grasty KC, Zentner IJ, Townsend TM, Bhuiya MW, Cocklin S, and Loll PJ
Journal of the American Chemical Society 134:4637-4645, 2012

"Conformational and structural features of HIV-1 gp120 underlying the dual receptor antagonism by cross-reactive neutralizing antibody m18"
Gift SK, Zentner IJ, Schon A, McFadden K, Umashankara M, Rajagopal S, Contarino M, Duffy C, Courter JR, Zhang MY, Gershoni JM, Cocklin S, Dimitrov DS, Smith AB 3rd, Freire E, and Chaiken IM
Biochemistry;50(14):2756-2768, 2011

"Introducing metallocene into a triazole peptide conjugate reduces its off-rate and enhances its affinity and antiviral potency for HIV-1 gp120"
Gopi H, Cocklin S, Pirrone V, McFadden K, Tuzer F, Zentner I, Ajith S, Baxter S, Jawanda N, Krebs FC, and Chaiken IM
Journal of Molecular Recognition. 22(2):169-174, 2009

"The V1-V3 region of a brain-derived HIV-1 envelope glycoprotein determines macrophage tropism, low CD4 dependence, increased fusogenicity and reduced sensitivity to entry inhibitors"
Rossi F, Querido B, Nimmagadda M, Cocklin S, Navas-Martín S, and Martín-Garcia J
Retrovirology Oct 6; 5:89, 2008

"Enhanced EGFR inhibition and distinct epitope recognition by EGFR antagonistic mAbs C225 and 425"
Kamat K, Donaldson JM, Kari C, Quadros MRD, Lelkes P, Chaiken I, Cocklin S, Williams JC, Papazoglou E, and Rodeck U
Cancer Biology & Therapeutics. 7(5):726-733, 2008

"Structural determinants for affinity enhancement of a dual antagonist peptide entry inhibitor of human immunodeficiency virus type-1 Envelope gp120"
Gopi, HN, Umashankara M, Pirrone,V., LaLonde, J, Madani N, Tuzer F, Baxter S, Zentner I, Cocklin S, Jawanda N, Miller, SR., Schön A, Klein JC., Freire E, Krebs, FC, Smith III, A.B., Sodroski, J, and Chaiken, I.
Journal of Medicinal Chemistry.51(9):2638-2647, 2008

"A recombinant allosteric lectin antagonist of HIV-1 Envelope gp120 interactions"
McFadden K, Cocklin S, Gopi HN, Baxter S, Ajith S, Mahmood N, Shattock R, Chaiken IM
Proteins: Structure, Function and Bioinformatics. 67(3):617-629, 2007

"Broad-spectrum anti-HIV potential of a peptide HIV-1 entry inhibitor"
Cocklin S*, Gopi HN, Querido B, Nimmagadda M, Kuriakose S, Cicala C, Ajith S, Baxter S, Arthos J, Martin-Garcia J, and Chaiken I (*corresponding author)
Journal of Virology. 81(7):3645-3648, 2007

"Antibody binding in proximity to retroviral envelope glycoproteins leads to a basal level of neutralization"
Yang X, Lipchina I, Cocklin S, Chaiken IM, and Sodroski J
Journal of Virology. 80(22):11404-1108, 2006

"Real-time monitoring of the membrane-binding and insertion properties of the cholesterol-dependent cytolysin anthrolysin O from Bacillus anthracis"
Cocklin S, Jost M, Robertson NM, Weeks SD, Weber H-W, Young E, Seal S, Zhang C, Mosser E, Loll PJ, Saunders AJ, Rest R, and Chaiken IM
Journal of Molecular Recognition. 19(4):354-362, 2006

"Interaction with CD4 and antibodies to CD4-induced epitopes of monomeric gp120 from a microglia-adapted human immunodeficiency virus type 1 isolate"
Martín-García J, Cocklin S, Chaiken IM, and González-Scarano F
Journal of Virology. 79(11):6703-6713 (2005)

"Modulation of the ligand binding properties of the transcription repressor NmrA by GATA-containing DNA and site-directed mutagenesis"
Lamb HK, Ren J, Park A, Johnson C, Leslie K, Cocklin S, Thompson P, Mee C, Cooper A, Stammers DK, and Hawkins AR
Protein Science. 13(12):3127-3138 (2004)

"Small molecule inhibitors of the HIV-1 envelope block receptor-induced conformational changes in the viral envelope glycoproteins"
Si Z, Madani N, Cox JM, Chruma JJ, Klein JC, Schon A, Phan N, Wang L, Biorn AC, Cocklin S, Chaiken I, Freire E, Smith AB, and Sodroski JG
Proceedings of the National Academy of Sciences USA. 101(14):5036-5041, 2004

"Mode of action for linear peptide inhibitors of HIV-1 gp120 interactions"
Biorn AC*, Cocklin S*, Madani N*, Si Z, Ivanovic T, Samanen J, Van Ryk DI, Pantophlet R, Burton DR, Freire E, Sodroski J, and Chaiken I
Biochemistry. 43(7):1928-1938, 2004
*Equal authorship

"Proteins, recognition networks and developing interfaces for macromolecular biosensing"
Sergi M, Zurawski J, Cocklin S, and Chaiken I
Journal of Molecular Recognition. 17(3):198-208, 2004

"The PDZ domains of the HtrA protease/chaperonin and the Tsp protease facilitate substrate binding"
Spiers A, Lamb HK, Cocklin S, Wheeler KA Budworth J, Dodds AL, Pallen MJ, Maskell DJ, Charles IG, and Hawkins AR
Journal of Biological Chemistry. 277(42):39443-39449, 2002

"The structure of the negative transcriptional regulator NmrA reveals a structural superfamily which includes the short-chain dehydrogenase/reductases"
Stammers DK, Ren J, Leslie K, Nichols CE, Lamb HK, Cocklin S, Dodds A, and Hawkins AR
EMBO Journal. 20(23):6619-6626, 2001

"Expression, purification and crystallization of Aspergillus nidulans NmrA, a negative regulatory protein involved in nitrogen-metabolite repression"
Nichols CE, Cocklin S, Dodds A, Ren J, Lamb H, Hawkins AR, and Stammers DK
Acta Crystallographica D Biological Crystallography. 57(11):1722-1725, 2001

Contact Information

Department of Biochemistry & Molecular Biology
245 North 15th Street
Mail Stop 497
Philadelphia, PA 19102
Phone: 215.762.7234
Fax: 215.762.4452