Molecular Dynamics Simulations in Drug Discovery and Drug Delivery

Saurabh, Suman; Sivakumar, Ponnurengam Malliappan; Perumal, Venkatesan; Khosravi, Arezoo; Sugumaran, Abimanyu; Prabhawathi, Veluchamy

doi:10.1007/978-3-030-36260-7_10

Cited by 16 publications

(11 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It may help to predict drug delivery prior experiments and, in consequence, allow minimizing the cost of drug design and development [ 18 ]. In the context of carrier-mediated drug release, the MD simulations can provide a detailed description of the mechanism of drug loading/release [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Influence of Terpene Type on the Release from an O/W Nanoemulsion: Experimental and Theoretical Studies

Miastkowska

Śliwa

2020

Molecules

View full text Add to dashboard Cite

The interaction between a drug molecule and its carrier’s components is an important factor which influences the drug release profile. For this purpose, molecular dynamics (MD) may be the in silico tool which can help to understand the mechanism of drug loading/release. The aim of this work is to explain the effect of interactions between different types of terpenes, namely perillyl alcohol, forskolin, ursolic acid, and the nanoemulsion droplet core, on the release by means of experimental and theoretical studies. The basic nanoemulsion was composed of caprylic/capric triglyceride as the oil phase, polysorbate 80 as the emulsifier, and water. The in vitro release tests from a terpene-loaded nanoemulsion were carried out to determine the release profiles. The behavior of terpenoids in the nanoemulsion was also theoretically investigated using the molecular dynamics method. The forskolin-loaded nanoemulsion showed the highest percentage of drug release (almost 80% w/w) in contrast to ursolic acid and perillyl alcohol-loaded nanoemulsions (about 53% w/w and 19% w/w, respectively). The results confirmed that the kinetic model of release was terpene-type dependent. The zero-order model was the best to describe the ursolic acid release profile, while the forskolin and the perillyl alcohol followed a first-order and Higuchi model, respectively. Molecular dynamics simulations, especially energetical analysis, confirmed that the driving force of terpenes diffusion from nanoemulsion interior was their interaction energy with a surfactant.

show abstract

Section: Introductionmentioning

confidence: 99%

Influence of Terpene Type on the Release from an O/W Nanoemulsion: Experimental and Theoretical Studies

Miastkowska

Śliwa

2020

Molecules

View full text Add to dashboard Cite

show abstract

“…Molecular dynamics (MD) simulations have played an important role in new drug discovery processes. 47 It is useful to examine the protein−ligand interactions and the conformational changes in proteins at the atomic level. 48 Remdesivir, compound 8, and compound-17 bound RdRp complexes were considered for the 30 ns MD simulation study.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Molecular dynamics (MD) simulations have played an important role in new drug discovery processes . It is useful to examine the protein–ligand interactions and the conformational changes in proteins at the atomic level .…”

Section: Resultsmentioning

confidence: 99%

Revealing the Inhibition Mechanism of RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2 by Remdesivir and Nucleotide Analogues: A Molecular Dynamics Simulation Study

2020

View full text Add to dashboard Cite

Antiviral drug therapy against SARS-CoV-2 is not yet established and posing a serious global health issue. Remdesivir is the first antiviral compound approved by the US FDA for the SARS-CoV-2 treatment for emergency use, targeting RNA-dependent RNA polymerase (RdRp) enzyme. In this work, we have examined the action of remdesivir and other two ligands screened from the library of nucleotide analogues using docking and molecular dynamics (MD) simulation studies. The MD simulations have been performed for all the ligand-bound RdRp complexes for the 30 ns time scale. This is one of the earlier reports to perform the MD simulations studies using the SARS-CoV-2 RdRp crystal structure (PDB ID 7BTF). The MD trajectories were analyzed and Molecular Mechanics Poisson−Boltzmann Surface Area (MM-PBSA) calculations were performed to calculate the binding free energy. The binding energy data reveal that compound-17 (−59.6 kcal/ mol) binds more strongly as compared to compound-8 (−46.3 kcal/mol) and remdesivir (−29.7 kcal/mol) with RdRp. The detailed analysis of trajectories shows that the remdesivir binds in the catalytic site and forms a hydrogen bond with the catalytic residues from 0 to 0.46 ns. Compound-8 binds in the catalytic site but does not form direct hydrogen bonds with catalytic residues. Compound-17 showed the formation of hydrogen bonds with catalytic residues throughout the simulation process. The MD simulation results such as hydrogen bonding, the center of mass distance analysis, snapshots at a different time interval, and binding energy suggest that compound-17 binds strongly with RdRp of SARS-CoV-2 and has the potential to develop as a new antiviral against COVID-19. Further, the frontier molecular orbital analysis and molecular electrostatic potential (MESP) iso-surface analysis using DFT calculations shed light on the superior binding of compound-17 with RdRp compared to remdesivir and compound-8. The computed as well as the experimentally reported pharmacokinetics and toxicity parameters of compound-17 is encouraging and therefore can be one of the potential candidates for the treatment of COVID-19.

show abstract

“…Molecular dynamics (MD) simulations have played a great supporting role to experimental methods in determining the details of molecular level processes that occur in biological systems. , With the advent of advanced computing platforms, increasing accuracy of the biomolecular force fields, and advanced simulation methods, the capability of MD simulation is increasing in this regard. Recently a billion-atom-large atomistic simulation of the chromatin fiber has been performed, allowing a glimpse of the DNA organization therein .…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Fuzzy Drug Targets: Disordered Proteins in the Drug-Discovery Realm

et al. 2023

Self Cite

View full text Add to dashboard Cite

Intrinsically disordered proteins (IDPs) and regions (IDRs) form a large part of the eukaryotic proteome. Contrary to the structure−function paradigm, the disordered proteins perform a myriad of functions in vivo. Consequently, they are involved in various disease pathways and are plausible drug targets. Unlike folded proteins, that have a defined structure and well carved out drug-binding pockets that can guide lead molecule selection, the disordered proteins require alternative drug-development methodologies that are based on an acceptable picture of their conformational ensemble. In this review, we discuss various experimental and computational techniques that contribute toward understanding IDP "structure" and describe representative pursuances toward IDP-targeting drug development. We also discuss ideas on developing rational drug design protocols targeting IDPs.

show abstract

Molecular Dynamics Simulations in Drug Discovery and Drug Delivery

Cited by 16 publications

References 82 publications

Influence of Terpene Type on the Release from an O/W Nanoemulsion: Experimental and Theoretical Studies

Influence of Terpene Type on the Release from an O/W Nanoemulsion: Experimental and Theoretical Studies

Revealing the Inhibition Mechanism of RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2 by Remdesivir and Nucleotide Analogues: A Molecular Dynamics Simulation Study

Fuzzy Drug Targets: Disordered Proteins in the Drug-Discovery Realm

Contact Info

Product

Resources

About