Accelerating COVID-19 Research Using Molecular Dynamics Simulation

Abstract

The COVID-19 pandemic has emerged as a global medico-socio-economic disaster. Given the lack of effective therapeutics against SARS-CoV-2, scientists are racing to disseminate suggestions for rapidly deployable therapeutic options, including drug repurposing and repositioning strategies. Molecular dynamics (MD) simulations have provided the opportunity to make rational scientific breakthroughs in a time of crisis. Advancements in these technologies in recent years have become an indispensable tool for scientists studying protein structure, function, dynamics, interactions, and drug discovery. Integrating the structural data obtained from high-resolution methods with MD simulations has helped in comprehending the process of infection and pathogenesis, as well as the SARS-CoV-2 maturation in host cells, in a short duration of time. It has also guided us to identify and prioritize drug targets and new chemical entities, and to repurpose drugs. Here, we discuss how MD simulation has been explored by the scientific community to accelerate and guide translational research on SARS-CoV-2 in the past year. We have also considered future research directions for researchers, where MD simulations can help fill the existing gaps in COVID-19 research.

Systematic virtual screening in search of SARS CoV-2 inhibitors against spike glycoprotein: pharmacophore screening, molecular docking, ADMET analysis and MD simulations

“…Molecular dynamics simulations have been recognized as significant tool to claim the stability of the ligand and to reveal macromolecular structure to function relationships in the field of drug discovery [ 65 – 68 ]. Henceforth, we performed the molecular dynamics (MD) simulations at various time points up to 10 ns using GROMACS 2020.1 to assess the stability of the hits into the complexes obtained from ADMET and Lipinski rules analysis [ 69 , 70 ].…”

Interface‐based design of the favipiravir‐binding site in SARS‐CoV‐2 RNA‐dependent RNA polymerase reveals mutations conferring resistance to chain termination

“…Second, as the Rosetta‐based interface design protocol aims to design mutants with improved binding affinity to favipiravir, a more appropriate design methodology and scoring function is required to scan for resistance mutations (designs that reduce binding affinity to a ligand). Long‐timescale molecular dynamics (MD) simulations may be performed for examining the mutational effects on the conformational dynamics and stability of the protein [ 52 ]. Despite these limitations, to validate that our design methodology correctly predicted the affinity‐attenuating designs interpreting the resistance mutations, we conducted adequate control experiments on a SARS‐CoV remdesivir‐resistant mutant, which is a chain‐termination drug.…”

Intelligent Resolution: Integrating Cryo-EM with AI-driven Multi-resolution Simulations to Observe the SARS-CoV-2 Replication-Transcription Machinery in Action

“…Multiple research teams have invested their best resources towards the common goal of characterizing viral components and their biological functions, thereby providing a sign-post for the future direction of the field (Alam and Higgins, 2020, Bárcena et al, 2021, Barrantes, 2021, Kim and Jung, 2021). Structural biology data, which provides the basis for rational design of all new medicines against human and animal disease, is now inherently multi-modal and multi-scale, requiring novel integrative approaches (AlQuraishi, 2019, Arantes et al, 2020, Jumper et al, 2021, Minkyung et al, 2021, Muratov et al, 2021, Padhi et al, 2021, Tunyasuvunakool et al, 2021, Zimmerman et al, 2020).…”