Computer-assisted identification of potential quinolone derivatives targeting Nipah virus glycoprotein attachment with human cell surface receptor ephrin-B2: Multistep virtual screening

Siyun Yang; Supratik Kar

doi:10.1016/j.compbiomed.2023.107240

Computer-assisted identification of potential quinolone derivatives targeting Nipah virus glycoprotein attachment with human cell surface receptor ephrin-B2: Multistep virtual screening

Comput Biol Med. 2023 Sep:163:107240. doi: 10.1016/j.compbiomed.2023.107240. Epub 2023 Jul 8.

Authors

Siyun Yang¹, Supratik Kar²

Affiliations

¹ Chemometrics and Molecular Modeling Laboratory, Department of Chemistry, Kean University, 1000 Morris Avenue, Union, NJ, 07083, USA.
² Chemometrics and Molecular Modeling Laboratory, Department of Chemistry, Kean University, 1000 Morris Avenue, Union, NJ, 07083, USA. Electronic address: skar@kean.edu.

PMID: 37442011
DOI: 10.1016/j.compbiomed.2023.107240

Abstract

Nipah Virus (NiV) is a single-stranded, negative-sense, highly lethal RNA virus. Even though NiV has close to 70-80% of mortality in India and Bangladesh, still there is no available US FDA-approved drug or vaccine. NiV attachment glycoprotein (NiV-G) is critical for NiV to invade the human cell where ephrinB2 which is a crucial membrane-bound ligand that acts as a target of NiV. Most of the research has been performed targeting NiV or human ephrin-B to date. Quinolone derivatives are proven scaffolds for many approved drugs used to treat various bacterial, viral respiratory tract, and urinary tract infections, and rheumatologic disorders such as systemic lupus erythematosus, rheumatoid arthritis. Therefore, we have tried to find potential drug molecules employing quinolone scaffold-based derivatives from PubChem targeting both NiV-G and ephrin-B2 protein. A total of 1500+ quinolone derivatives were obtained from PubChem which were screened based on Drug Likeness followed by being subjected to XP docking employing Schrödinger software. The top ten best molecules were then chosen for their absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling based on the docking score ranking. Further, the top five molecules were selected for 200ns molecular dynamics (MD) simulation study with Desmond module followed by MM-GBSA study by Prime module of Schrödinger. The exhaustive analysis leads us to the top three probable lead drug molecules for NiV are PubChem CID 23646770, an analog of PubChem CID 67726448, and PubChem CID 10613168 which have predicted K_i values of 0.480 μm, 0.785 μm, and 0.380 μm, respectively. These proposed molecules can be the future drugs targeting NiV-G and human ephrin-B2 which requires further in vivo validation.

Keywords: ADMET; CADD; Docking; Ephrin-B2; Molecular dynamics; Nipah virus; Quinolone derivative.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Computers
Ephrin-B2 / genetics
Ephrin-B2 / metabolism
Glycoproteins / metabolism
Humans
Nipah Virus* / metabolism
Quinolones* / metabolism
Receptors, Cell Surface / metabolism

Substances

Ephrin-B2
Quinolones
Receptors, Cell Surface
Glycoproteins