Predicting the Activity of Boronate Inhibitors Against Metallo-β-lactamase Enzymes

Authors

DOI:

https://doi.org/10.14529/jsfi220202

Keywords:

metallo-β-lactamase, boronate inhibitors, MD, QM/MM MD, quantum theory of atoms in molecules (QTAIM), GPU-accelerated algorithms

Abstract

Potency of boronate inhibitors against metallo-β-lactamases (MβLs) has been found to be dependent on the electrophilicity of the boron atom. It forms a covalent bond with the oxygen atom of the catalytic OH− ion in the active site of the enzyme. The ability of the boronate inhibitor to influence the protein conformation also affects the binding potency. Molecular dynamics (MD) simulations of cyclic and non-cyclic boronate complexes with NDM-1 MβL show their higher impact on the inhibitor efficiency compared with the electrophilicity of the boron atom. Therefore, we focus on the hardware impact on the computational speedup of the GPU-accelerated MD. Using this data, we propose a comprehensive protocol for in silico prediction of the activity of boronate molecules against MβL enzymes, which includes MD simulations, combined quantum mechanics / molecular mechanics (QM/MM) computations and molecular dynamics simulations with the QM/MM potentials (QM/MM MD).

References

Gaussian09, Gaussian, Inc., Wallingford CT, 2016, https://gaussian.com

P1 Single and Multiple Ascending Dose (SAD/MAD) Study of IV QPX7728 Alone and Combined With QPX2014 in NHV, https://clinicaltrials.gov/ct2/show/NCT04380207

R.E.D. Server, https://upjv.q4md-forcefieldtools.org/REDServer-Development/

Adamo, C., Barone, V.: Toward reliable density functional methods without adjustable parameters: The PBE0 model. The Journal of Chemical Physics 110(13), 6158–6170 (1999). https://doi.org/10.1063/1.478522

Bader, R.F.W.: Atoms in Molecules. Quantum Theory. International series of monographs on chemistry, Clarendon Press (1990)

Best, R.B., Zhu, X., Shim, J., et al.: Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ1 and χ2 dihedral angle. Journal of Chemical Theory and Computation 8(9), 3257–3273 (2012). https://doi.org/10.1021/ct300400x

Bonomo, R.A.: β-Lactamases: a focus on current challenges. Cold Spring Harbor Perspectives in Medicine 7(1), a025239 (2017). https://doi.org/10.1101/cshperspect.a025239

Bush, K.: Past and present perspectives on β-lactamases. Antimicrobial Agents and Chemotherapy 62(10), e01076–18 (2018). https://doi.org/10.1128/AAC.01076-18

Cahill, S., Cain, R., Wang, D.Y., et al.: Cyclic boronates inhibit all classes of β-lactamases. Antimicrobial Agents and Chemotherapy 61(4), e02260–16 (2017). https://doi.org/10.1128/AAC.02260-16

Cendron, L., Quotadamo, A., Maso, L., et al.: X-ray Crystallography Deciphers the Activity of Broad-Spectrum Boronic Acid β-Lactamase Inhibitors. ACS Medicinal Chemistry Letters 10(4), 650–655 (2019). https://doi.org/10.1021/acsmedchemlett.8b00607

Cornell, W.D., Cieplak, P., Bayly, C.I., et al.: A second generation force field for the simulation of proteins, nucleic acids, and organic molecules J. Am. Chem. Soc. 1995, 117, 5179–5197. Journal of the American Chemical Society 118(9), 2309–2309 (1996). https: //doi.org/10.1021/ja955032e

Dortet, L., Poirel, L., Nordmann, P.: Worldwide Dissemination of the NDM-Type Carbapenemases in Gram-Negative Bacteria. BioMed Research International 2014, 1–12 (2014). https://doi.org/10.1155/2014/249856

Dupradeau, F.Y., Pigache, A., Zaffran, T., et al.: The R.E.D. tools: advances in RESP and ESP charge derivation and force field library building. Physical Chemistry Chemical Physics 12(28), 7821–7839 (2010). https://doi.org/10.1039/C0CP00111B

Espinosa, E., Molins, E.: Retrieving interaction potentials from the topology of the electron density distribution: The case of hydrogen bonds. The Journal of Chemical Physics 113(14), 5686–5694 (2000). https://doi.org/10.1063/1.1290612

Espinosa, E., Molins, E., Lecomte, C.: Hydrogen bond strengths revealed by topological analyses of experimentally observed electron densities. Chemical Physics Letters 285(3-4), 170–173 (1998). https://doi.org/10.1016/S0009-2614(98)00036-0

Gowers, R.J., Linke, M., Barnoud, J., et al.: MDAnalysis: A Python Package for the Rapid Analysis of Molecular Dynamics Simulations. Proceedings of the 15th Python in science conference pp. 98–105 (2016). https://doi.org/10.25080/Majora-629e541a-00e

Grabowski, S.J.: Intramolecular Hydrogen Bond Energy and Its Decomposition—O–H∙∙∙O Interactions. Crystals 11(1), 22935–22952 (2020). https://doi.org/10.3390/cryst11010005

Grimme, S., Antony, J., Ehrlich, S., Krieg, H.: A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. The Journal of Chemical Physics 132(15), 154104 (2010). https://doi.org/10.1063/1.3382344

Hariharan, P.C., Pople, J.A.: The influence of polarization functions on molecular orbital hydrogenation energies. Theoretica Chimica Acta 28(3), 213–222 (1973). https://doi.org/10.1007/BF00533485

Hecker, S.J., Reddy, K.R., Lomovskaya, O., et al.: Discovery of Cyclic Boronic Acid QPX7728, an Ultrabroad-Spectrum Inhibitor of Serine and Metallo-β-lactamases. Journal of Medicinal Chemistry 63(14), 7491–7507 (2020). https://doi.org/10.1021/acs.jmedchem.9b01976

Hehre, W.J., Ditchfield, R., Pople, J.A.: Self-Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian-Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules. The Journal of Chemical Physics 56(5), 2257–2261 (1972). https:// doi.org/10.1063/1.1677527

Hirshfeld, F.: Bonded-atom fragments for describing molecular charge densities. The Journal of Physical Chemistry A 44(2), 129–138 (1977). https://doi.org/10.1007/BF00549096

Huang, J., Rauscher, S., Nawrocki, G., et al.: CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nature Methods 14(1), 71–73 (2017). https: //doi.org/10.1038/nmeth.4067

Humphrey, W., Dalke, A., Schulten, K.: VMD: Visual molecular dynamics. Journal of Molecular Graphics 14(1), 33–38 (1996). https://doi.org/10.1016/0263-7855(96)00018-5

Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., et al.: Comparison of simple potential functions for simulating liquid water. The Journal of Chemical Physics 79(2), 926–935 (1983). https://doi.org/10.1063/1.445869

Krajnc, A., Brem, J., Hinchliffe, P., et al.: Bicyclic boronate VNRX-5133 inhibits metalloand serine-β-lactamases. Journal of Medicinal Chemistry 62(18), 8544–8556 (2019). https: //doi.org/10.1021/acs.jmedchem.9b00911

Krivitskaya, A.V., Khrenova, M.G.: Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling. Molecules 26(7), 2026 (2021). https://doi.org/10.3390/molecules26072026

Lence, E., González-Bello, C.: Bicyclic Boronate β-Lactamase Inhibitors: The Present Hope against Deadly Bacterial Pathogens. Advanced Therapeutics 4(5), 2000246 (2021). https: //doi.org/10.1002/adtp.202000246

Lomovskaya, O., Tsivkovski, R., Nelson, K., et al.: Spectrum of beta-lactamase inhibition by the cyclic boronate QPX7728, an ultrabroad-spectrum beta-lactamase inhibitor of serine and metallo-beta-lactamases: enhancement of activity of multiple antibiotics against isogenic strains expressing single beta-lactamases. Antimicrobial Agents and Chemotherapy 64(6), e00212–20 (2020). https://doi.org/10.1128/AAC.00212-20

Lu, T., Chen, F.: Multiwfn: A multifunctional wavefunction analyzer. Journal of Computational Chemistry 33(5), 580–592 (2012). https://doi.org/10.1002/jcc.22885

MacKerell, A.D., Bashford, D., Bellott, M., et al.: All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins. The Journal of Physical Chemistry B 102(18), 3586–3616 (1998). https://doi.org/10.1021/jp973084f

MacKerell, A.D., Feig, M., Brooks, C.L.: Improved Treatment of the Protein Backbone in Empirical Force Fields. Journal of the American Chemical Society 126(3), 698–699 (2004). https://doi.org/10.1021/ja03695

Mata, I., Alkorta, I., Espinosa, E., Molins, E.: Relationships between interaction energy, intermolecular distance and electron density properties in hydrogen bonded complexes under external electric fields. Chemical Physics Letters 507(1-3), 185–189 (2011). https://doi.org/10.1016/j.cplett.2011.03.055

Melo, M.C.R., Bernardi, R.C., Rudack, T., et al.: NAMD goes quantum: an integrative suite for hybrid simulations. Nature Methods 15(5), 351–354 (2018). https://doi.org/10.1038/nmeth.4638

Michaud-Agrawal, N., Denning, E.J., Woolf, T.B., Beckstein, O.: MDAnalysis: A toolkit for the analysis of molecular dynamics simulations. Journal of Computational Chemistry 32(10), 2319–2327 (2011). https://doi.org/10.1002/jcc.21787

Mojica, M.F., Rossi, M.A., Vila, A.J., Bonomo, R.A.: The urgent need for metallo-β-lactamase inhibitors: an unattended global threat. The Lancet Infectious Diseases 22(1), e28–e34 (2022). https://doi.org/10.1016/S1473-3099(20)30868-9

Novais, A., Ferraz, R.V., Viana, M., et al.: NDM-1 Introduction in Portugal through a ST11 KL105 Klebsiella pneumoniae Widespread in Europe. Antibiotics 11(1), 92 (2022). https://doi.org/10.3390/antibiotics11010092

Oláh, J., Van Alsenoy, C., Sannigrahi, A.B.: Condensed Fukui Functions Derived from Stockholder Charges: Assessment of Their Performance as Local Reactivity Descriptors. The Journal of Physical Chemistry A 106(15), 3885–3890 (2002). https://doi.org/10.1021/jp014039h

Osei Sekyere, J.: Current State of Resistance to Antibiotics of Last-Resort in South Africa: A Review from a Public Health Perspective. Frontiers in Public Health 4, 209 (2016). https://doi.org/10.3389/fpubh.2016.00209

Palacios, A.R., Rossi, M.A., Mahler, G.S., Vila, A.J.: Metallo-β-lactamase inhibitors inspired on snapshots from the catalytic mechanism. Biomolecules 10(6), a025239 (2020). https://doi.org/10.3390/biom10060854

Parkova, A., Lucic, A., Krajnc, A., et al.: Broad spectrum β-lactamase inhibition by a thioether substituted bicyclic boronate. ACS Infectious Diseases 6(6), 1398–1404 (2019). https://doi.org/10.1021/acsinfecdis.9b00330

Parkova, A., Lucic, A., Krajnc, A., et al.: A 2018-2019 patent review of metallo betalactamase inhibitors. ACS Infectious Diseases 30(7), 541–555 (2020). https://doi.org/10.1080/13543776.2020.1767070

Phillips, J.C., Hardy, D.J., Maia, J.D.C., et al.: Scalable molecular dynamics on CPU and GPU architectures with NAMD. The Journal of Chemical Physics 153(4), 044130 (2020). https://doi.org/10.1063/5.0014475

Phillips, L.C., Braun, R., Wang, W., et al.: Scalable molecular dynamics with NAMD. Journal of Computational Chemistry 26(16), 1781–1802 (2005). https://doi.org/10.1002/ jcc.20289

Sabet, M., Tarazi, Z., Griffith, D.C.: In vivo activity of QPX7728, an ultrabroad-spectrum beta-lactamase inhibitor, in combination with beta-lactams against carbapenem-resistant Klebsiella pneumoniae. Antimicrobial Agents and Chemotherapy 64(11), e01267–20 (2020). https://doi.org/10.1128/AAC.01267-20

Santucci, M., Spyrakis, F., Cross, S., et al.: Computational and biological profile of boronic acids for the detection of bacterial serine- and metallo-β-lactamases. Scientific reports 7(17716), 1–15 (2017). https://doi.org/10.1038/s41598-017-17399-7

Seritan, S., Bannwarth, C., Fales, B.S., et al.: TeraChem: A graphical processing unitaccelerated electronic structure package for largescale ab initio molecular dynamics. Wiley Interdisciplinary Reviews: Computational Molecular Science 11(2), e1494 (2021). https://doi.org/10.1002/wcms.1494

Shahi, A., Arunan, E.: Hydrogen bonding, halogen bonding and lithium bonding: an atoms in molecules and natural bond orbital perspective towards conservation of total bond order, inter- and intra-molecular bonding. Physical Chemistry Chemical Physics 16(4), 22935–22952 (2014). https://doi.org/10.1039/C4CP02585G

Shi, C., Chen, J., Kang, X., et al.: Approaches for the discovery of metallo-β-lactamase inhibitors: A review. Chemical Biology & Drug Design 94(2), 1427–1440 (2019). https://doi.org/10.1111/cbdd.13526

Tehrani, K.H., Martin, N.I.: β-lactam/β-lactamase inhibitor combinations: an update. MedChemComm 9(9), 1439–1456 (2018). https://doi.org/10.1039/c8md00342d

Thapa, S., Adhikari, N., Shah, A.K., et al.: Detection of NDM-1 and VIM genes in carbapenem-resistant Klebsiella pneumoniae isolates from a tertiary health-care center in Kathmandu, Nepal. Chemotherapy 66(5-6), 199–209 (2021). https://doi.org/10.1159/000518256

Tooke, C.L., Hinchliffe, P., Bragginton, E.C., et al.: Lactamases and β-Lactamase Inhibitors in the 21st Century. Journal of Molecular Biology 431(18), 3472–3500 (2019). https://doi.org/10.1016/j.jmb.2019.04.002

Tsivkovski, R., Totrov, M., Lomovskaya, O.: Biochemical characterization of QPX7728, a new ultrabroad-spectrum beta-lactamase inhibitor of serine and metallo-beta-lactamases. Antimicrobial Agents and Chemotherapy 64(6), e00130–20 (2020). https://doi.org/10.1128/AAC.00130-20

Valiev, M., Bylaska, J., Govind, N., et al.: NWChem: A comprehensive and scalable opensource solution for large scale molecular simulations. Computer Physics Communications 181(9), 1477–1489 (2010). https://doi.org/10.1016/j.cpc.2010.04.018

Vanommeslaeghe, K., Hatcher, E., Acharya, C., et al.: CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. Journal of Computational Chemistry 31(4), 671–690 (2009). https://doi.org/10.1002/jcc.21367

Vanquelef, E., Simon, S., Marquant, G., et al.: R.E.D. Server: a web service for deriving RESP and ESP charges and building force field libraries for new molecules and molecular fragments. Nucleic Acids Research 39, W511–W517 (2011). https://doi.org/10.1093/nar/gkr288

Vázquez-Ucha, J.C., Rodríguez, D., Lasarte-Monterrubio, C., et al.: 6-Halopyridylmethylidene Penicillin-Based Sulfones Efficiently Inactivate the Natural Resistance of Pseudomonas aeruginosa to β-Lactam Antibiotics. Journal of Medicinal Chemistry 64(9), 6310–6328 (2021). https://doi.org/10.1021/acs.jmedchem.1c00369

Venkata, K.C.N., Ellebrecht, M., Tripathi, S.K.: Efforts towards the inhibitor design for New Delhi metallo-beta-lactamase (NDM-1). European Journal of Medicinal Chemistry 225(5), 113747 (2021). https://doi.org/10.1016/j.ejmech.2021.113747

Voevodin, V.V., Antonov, A.S., Nikitenko, D.A., et al.: Supercomputer Lomonosov-2: Large Scale, Deep Monitoring and Fine Analytics for the User Community. Supercomputing Frontiers and Innovations 6(2), 4–11 (2019). https://doi.org/10.14529/jsfi190201

Yu, W., He, X., Vanommeslaeghe, K., MacKerell, A.D.: Extension of the CHARMM general force field to sulfonyl-containing compounds and its utility in biomolecular simulations. Journal of Computational Chemistry 33(31), 2451–2468 (2012). https://doi.org/10.1002/jcc.23067

Downloads

Published

2022-11-07

How to Cite

Levina, E. O., Khrenova, M. G., & Tsirelson, V. G. (2022). Predicting the Activity of Boronate Inhibitors Against Metallo-β-lactamase Enzymes. Supercomputing Frontiers and Innovations, 9(2), 14–32. https://doi.org/10.14529/jsfi220202