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. 2022;40(22):12209-12220.
doi: 10.1080/07391102.2021.1969281. Epub 2021 Aug 31.

Myxobacterial depsipeptide chondramides interrupt SARS-CoV-2 entry by targeting its broad, cell tropic spike protein

Rey Arturo Fernandez  1 , Mark Tristan Quimque  1   2   3 , Kin Israel Notarte  4 , Joe Anthony Manzano  1   5 , Delfin Yñigo Pilapil 4th  1   5 , Von Novi de Leon  1   5 , John Jeric San Jose  1 , Omar Villalobos  6 , Nisha Harur Muralidharan  7 , M Michael Gromiha  7 , Simone Brogi  8 , Allan Patrick G Macabeo  1
Affiliations

Myxobacterial depsipeptide chondramides interrupt SARS-CoV-2 entry by targeting its broad, cell tropic spike protein

Rey Arturo Fernandez et al. J Biomol Struct Dyn. 2022.

Abstract

The severity of the COVID-19 pandemic has necessitated the search for drugs against SARS-CoV-2. In this study, we explored via in silico approaches myxobacterial secondary metabolites against various receptor-binding regions of SARS-CoV-2 spike which are responsible in recognition and attachment to host cell receptors mechanisms, namely ACE2, GRP78, and NRP1. In general, cyclic depsipeptide chondramides conferred high affinities toward the spike RBD, showing strong binding to the known viral hot spots Arg403, Gln493 and Gln498 and better selectivity compared to most host cell receptors studied. Among them, chondramide C3 (1) exhibited a binding energy which remained relatively constant when docked against most of the spike variants. Chondramide C (2) on the other hand exhibited strong affinity against spike variants identified in the United Kingdom (N501Y), South Africa (N501Y, E484K, K417N) and Brazil (N501Y, E484K, K417T). Chondramide C6 (9) showed highest BE towards GRP78 RBD. Molecular dynamics simulations were also performed for chondramides 1 and 2 against SARS-CoV-2 spike RBD of the Wuhan wild-type and the South African variant, respectively, where resulting complexes demonstrated dynamic stability within a 120-ns simulation time. Protein-protein binding experiments using HADDOCK illustrated weaker binding affinity for complexed chondramide ligands in the RBD against the studied host cell receptors. The chondramide derivatives in general possessed favorable pharmacokinetic properties, highlighting their potential as prototypic anti-COVID-19 drugs limiting viral attachment and possibly minimizing viral infection.Communicated by Ramaswamy H. Sarma.

Keywords: Antiviral agents; COVID-19; SARS-CoV-2 spike proteins and variants; molecular docking; protein-protein interactions.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1.
Figure 1.
Top scoring chondramides 1–8 against spike receptor-binding domain.
Figure 2.
Figure 2.
Three dimensional (left) and schematic representations (right) of (a) chondramide C3 (1) against wild-type, (b) chondramide C (2) against N501Y, and (c) chondramide C (2) against E484K SARS-CoV-2 spike variants.
Figure 3.
Figure 3.
Three dimensional (left) and schematic representations (right) of chondramide C (2) against (a) South African (N501Y-E484K-K417N) and (b) Brazilian (N501Y-E484K-K417T) SARS-CoV-2 variants.
Figure 4.
Figure 4.
(a) Structure of chondramide C6 (9), (b) Three dimensional and (c) 2 D animated representation of chondramide C6 (9) against SARS-CoV-2 S protein receptor-binding domain to GRP78.
Figure 5.
Figure 5.
Molecular dynamics simulations of chondramide C3-wild-type SARS-CoV-2 spike complex. (a) root mean square deviation (RMSD), (b) root mean square fluctuation (RMSF), (c) radius of gyration (Rg) and (d) number of hydrogen bonds.
Figure 6.
Figure 6.
Molecular dynamics simulations of chondramide C (2)-wild-type SARS-CoV-2 spike complex (black) and chondramide C (2)-South African variant complex (red). (a) root mean square deviation (RMSD), (b) root mean square fluctuation (RMSF), (c) radius of gyration (Rg) and (d) number of hydrogen bonds.
See this image and copyright information in PMC

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