scholarly journals Understanding the Pyrimethamine Drug Resistance Mechanism via Combined Molecular Dynamics and Dynamic Residue Network Analysis

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 904 ◽  
Author(s):  
Arnold Amusengeri ◽  
Rolland Bantar Tata ◽  
Özlem Tastan Bishop
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Network Analysis ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Point Mutations ◽  
Md Simulations ◽  
Conformational Plasticity ◽  
New Perspective ◽  
The Impact

In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity. Generally, mutations led to reduced binding affinity to pyrimethamine and increased conformational plasticity of DHFR. Next, dynamic residue network analysis (DRN) was applied to determine the impact of mutations and pyrimethamine binding on communication dispositions of DHFR residues. DRN revealed residues with distinctive communication profiles, distinguishing WT from drug-resistant mutants as well as pyrimethamine-bound from pyrimethamine-free models. Our results provide a new perspective on the understanding of mutation-induced drug resistance.

Revealing the binding and drug resistance mechanism of amprenavir, indinavir, ritonavir, and nelfinavir complexed with HIV-1 protease due to double mutations G48T/L89M by molecular dynamics simulations and free energy analyses

2020 ◽  
Vol 22 (8) ◽  
pp. 4464-4480
Author(s):  
Rui-Ge Wang ◽  
Hong-Xing Zhang ◽  
Qing-Chuan Zheng
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Resistance Mechanism ◽  
Md Simulations ◽  
Resistance Mechanisms ◽  
Dynamics Simulations ◽  
Hiv 1

MD simulations, MM-PBSA, and SIE analyses were used to investigate the drug resistance mechanisms of two mutations G48T and L89M in HIV-1 protease toward four inhibitors.

scholarly journals Molecular modeling study on the drug resistance mechanism of NS5B polymerase to TMC647055

2016 ◽  
Vol 94 (2) ◽  
pp. 147-158 ◽  
Author(s):  
Huiqun Wang ◽  
Wei Cui ◽  
Chenchen Guo ◽  
Bo-Zhen Chen ◽  
Mingjuan Ji
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Rational Design ◽  
Binding Free Energy ◽  
Resistance Mechanism ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Free Energy Decomposition ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

NS5B polymerase plays an important role in viral replication machinery. TMC647055 (TMC) is a novel and potent non-nucleoside inhibitor of the HCV NS5B polymerase. However, mutations that result in drug resistance to TMC have been reported. In this study, we used molecular dynamics (MD) simulations, binding free energy calculations, and free energy decomposition to investigate the drug resistance mechanism of HCV to TMC resulting from L392I, P495T, P495S, and P495L mutations in NS5B polymerase. From the calculated results we determined that the decrease in the binding affinity between TMC and NS5BL392I polymerase is mainly caused by the extra methyl group at the CB atom of Ile. The polarity of the side-chain of residue 495 has no distinct influence on residue 495 binding with TMC, whereas the smaller size of the side-chain of residue 495 causes a substantial decrease in the van der Walls interaction between TMC and residue 495. Moreover, the longer length of the side-chain of residue 495 has a significant effect on the electrostatic interaction between TMC and Arg-503. Finally, we performed the same calculations and detailed analysis on other 3 mutations (L392V, P495V, and P495I). The results further confirmed our conclusions. The computational results not only reveal the drug resistance mechanism between TMC647055 and NS5B polymerase, but also provide valuable information for the rational design of more potent non-nucleoside inhibitors targeting HCV NS5B polymerase.

scholarly journals Structural Properties of G,T-Parallel Duplexes

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Anna Aviñó ◽  
Elena Cubero ◽  
Raimundo Gargallo ◽  
Carlos González ◽  
Modesto Orozco ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Properties ◽  
Theoretical Calculations ◽  
Md Simulations ◽  
Theoretical Studies ◽  
Duplex Structure ◽  
Strong Stabilization ◽  
The Stability ◽  
The Impact

The structure of G,T-parallel-stranded duplexes of DNA carrying similar amounts of adenine and guanine residues is studied by means of molecular dynamics (MD) simulations and UV- and CD spectroscopies. In addition the impact of the substitution of adenine by 8-aminoadenine and guanine by 8-aminoguanine is analyzed. The presence of 8-aminoadenine and 8-aminoguanine stabilizes the parallel duplex structure. Binding of these oligonucleotides to their target polypyrimidine sequences to form the corresponding G,T-parallel triplex was not observed. Instead, when unmodified parallel-stranded duplexes were mixed with their polypyrimidine target, an interstrand Watson-Crick duplex was formed. As predicted by theoretical calculations parallel-stranded duplexes carrying 8-aminopurines did not bind to their target. The preference for the parallel-duplex over the Watson-Crick antiparallel duplex is attributed to the strong stabilization of the parallel duplex produced by the 8-aminopurines. Theoretical studies show that the isomorphism of the triads is crucial for the stability of the parallel triplex.

Molecular Dynamics Study Of Surface Morphological Evolution By Cluster Impacts

2003 ◽  
Vol 792 ◽  
Author(s):  
Takaaki Aoki ◽  
Jiro Matsuo ◽  
Isao Yamada
Keyword(s):  
Molecular Dynamics ◽  
Ion Irradiation ◽  
Morphological Evolution ◽  
Md Simulations ◽  
Impact Area ◽  
Cluster Ion ◽  
Dynamics Simulations ◽  
Large Clusters ◽  
The Hill ◽  
The Impact

ABSTRACTIn order to understand the characteristics of surface modification process with cluster ion irradiation, molecular dynamics simulations of Ar cluster impacting on Si surface with various surface structures were carried out. It was found that the surface morphology is dynamically deformed with only one cluster impact and the impact process of cluster is different depending on the local surface structure. For example, when an Ar2000 cluster accelerated with 20keV impacted on the convex point of the surface, the hill was compressed and the impact area was smoothed. At the impact on a concave point, a deeper crater was formed compared with the impact on a flat surface. On the other hand, the MD simulations of sequential impacts of large clusters were performed. It was found that the small tip structures on the surface could be removed easily with cluster irradiation. It was shown that surface roughness converges to 15∼20Å and this value agrees with the result obtained by single impact of cluster.

Molecular Dynamics Simulations of Cluster-size Effect on Sputtering Process with Reactive Gas Cluster Ions

2005 ◽  
Vol 908 ◽  
Author(s):  
Takaaki Aoki ◽  
Jiro Matsuo
Keyword(s):  
Molecular Dynamics ◽  
Size Effect ◽  
Cluster Size ◽  
Incident Energy ◽  
Md Simulations ◽  
Cluster Ions ◽  
Experimental Conditions ◽  
Near Surface ◽  
The Impact ◽  
Reactive Cluster

AbstractTo investigate the size-effect of reactive clusters on sputtering processes, we performed molecular dynamics (MD) simulations of reactive cluster ions with various sizes impacting on solid targets. Various sizes of fluorine clusters, (F2)30, (F2)300 and (F2)3000, were irradiated on a Si(100) target at the same total incident energy of 6 keV. These clusters were irradiated on the same target one after another in order to reproduce real experimental conditions such as the accumulation of fluorine atoms in the target. The MD simulations of sequential cluster impacts enabled to perform various statistical analyses regarding the sputtered particles. The study of cluster size distributions showed that the sputtering process by reactive cluster ion impact has similarity with the emission from quasi-liquid materials excited to hyper-thermal conditions by ion bombardment. However, the major sputtered particles were different with each other; Si for (F2)30 (100 eV/atom), SiF2 for (F2)300 (10 eV/atom), and SiF3 for (F2)3000 (1 eV/atom). At the impact of a large size cluster with low incident energy, a large number of Si-F bondings were generated at the cluster-target interface surface, which enhances formation of volatile SiFx compounds with many fluorine atoms. In contrast, a small cluster with high kinetic energy-per-atom could cause the formation of numerous energetic surface atoms at the near surface region, which could be sputtered without being well fluoridated.

scholarly journals Impact of an Intervention to Control Imipenem-Resistant Acinetobacter baumannii and Its Resistance Mechanisms: An 8-Year Survey

2021 ◽  
Vol 11 ◽  
Author(s):  
Lida Chen ◽  
Pinghai Tan ◽  
Jianming Zeng ◽  
Xuegao Yu ◽  
Yimei Cai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acinetobacter Baumannii ◽  
Bacterial Resistance ◽  
Efflux Pump ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Multi Drug Resistance ◽  
Minimal Inhibitory Concentrations ◽  
Resistance Rates ◽  
The Impact

BackgroundThis study aimed to examine the impact of an intervention carried out in 2011 to combat multi-drug resistance and outbreaks of imipenem-resistant Acinetobacter baumannii (IRAB), and to explore its resistance mechanism.MethodsA total of 2572 isolates of A. baumannii, including 1673 IRAB isolates, were collected between 2007 and 2014. An intervention was implemented to control A. baumannii resistance and outbreaks. Antimicrobial susceptibility was tested by calculating minimal inhibitory concentrations (MICs), and outbreaks were typed using pulsed-field gel electrophoresis (PFGE). Resistance mechanisms were explored by polymerase chain reaction (PCR) and whole genome sequencing (WGS).ResultsFollowing the intervention in 2011, the resistance rates of A. baumannii to almost all tested antibiotics decreased, from 85.3 to 72.6% for imipenem, 100 to 80.8% for ceftriaxone, and 45.0 to 6.9% for tigecycline. The intervention resulted in a decrease in the number (seven to five), duration (8–3 months), and departments (five to three) affected by outbreaks; no outbreaks occurred in 2011. After the intervention, only blaAMPC (76.47 to 100%) and blaTEM–1 (75.74 to 96.92%) increased (P < 0.0001); whereas blaGES–1 (32.35 to 3.07%), blaPER–1 (21.32 to 1.54%), blaOXA–58 (60.29 to 1.54%), carO (37.50 to 7.69%), and adeB (9.56 to 3.08%) decreased (P < 0.0001). Interestingly, the frequency of class B β-lactamase genes decreased from 91.18% (blaSPM–1) and 61.03% (blaIMP–1) to 0%, while that of class D blaOXA–23 increased to 96.92% (P < 0.0001). WGS showed that the major PFGE types causing outbreaks each year (type 01, 11, 18, 23, 26, and 31) carried the same resistance genes (blaKPC–1, blaADC–25, blaOXA–66, and adeABC), AdeR-S mutations (G186V and A136V), and a partially blocked porin channel CarO. Meanwhile, plasmids harboring blaOXA–23 were found after the intervention.ConclusionThe intervention was highly effective in reducing multi-drug resistance of A. baumannii and IRAB outbreaks in the long term. The resistance mechanisms of IRAB may involve genes encoding β-lactamases, efflux pump overexpression, outer membrane porin blockade, and plasmids; in particular, clonal spread of blaOXA–23 was the major cause of outbreaks. Similar interventions may also help reduce bacterial resistance rates and outbreaks in other hospitals.

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