scholarly journals Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021 ◽  
Vol 14 (10) ◽  
pp. 1062
Author(s):  
Tomasz Róg ◽  
Mykhailo Girych ◽  
Alex Bunker
Keyword(s):  
Molecular Dynamics ◽  
Drug Design ◽  
Active Site ◽  
Lipid Membranes ◽  
Md Simulation ◽  
Lipid Membrane ◽  
Pharmaceutical Research ◽  
Specific Protein ◽  
Design Tool ◽  
Drug Molecules

We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

Structure guided design and binding analysis of EGFR inhibiting analogues of erlotinib and AEE788 using ensemble docking, molecular dynamics and MM-GBSA

RSC Advances ◽  
2016 ◽  
Vol 6 (70) ◽  
pp. 65725-65735 ◽  
Author(s):  
Vishnu K. Sharma ◽  
Prajwal P. Nandekar ◽  
Abhay Sangamwar ◽  
Horacio Pérez-Sánchez ◽  
Subhash Mohan Agarwal
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Md Simulation ◽  
Egfr Inhibitors ◽  
Egfr Inhibitor ◽  
Inhibitor Binding ◽  
Ensemble Docking ◽  
Binding Analysis

The study uncovers an essential pharmacophoric requirement for design of new EGFR inhibitors. Docking and MD simulation confirmed that the occupancy of an additional sub-pocket in the EGFR active site is important for tight EGFR-inhibitor binding.

scholarly journals Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach

2021 ◽  
Vol 11 ◽  
Author(s):  
Prem Prakash Kushwaha ◽  
Atul Kumar Singh ◽  
Tanya Bansal ◽  
Akansha Yadav ◽  
Kumari Sunita Prajapati ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Active Site ◽  
Md Simulation ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Kcal Mole ◽  
Hydrogen Bond Formation ◽  
Docking Score

The present study explores the SARS-CoV-2 drugable target inhibition efficacy of phytochemicals from Indian medicinal plants using molecular docking, molecular dynamics (MD) simulation, and MM-PBSA analysis. A total of 130 phytochemicals were screened against SARS-CoV-2 Spike (S)-protein, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). Result of molecular docking showed that Isoquercetin potentially binds with the active site/protein binding site of the Spike, RdRP, and Mpro targets with a docking score of -8.22, -6.86, and -9.73 kcal/mole, respectively. Further, MS 3, 7-Hydroxyaloin B, 10-Hydroxyaloin A, showed -9.57, -7.07, -8.57 kcal/mole docking score against Spike, RdRP, and Mpro targets respectively. The MD simulation was performed to study the favorable confirmation and energetically stable complex formation ability of Isoquercetin and 10-Hydroxyaloin A phytochemicals in Mpro-unbound/ligand bound/standard inhibitor bound system. The parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape, principal component analysis showed that the lead phytochemicals form stable and energetically stabilized complex with the target protein. Further, MM-PBSA analysis was performed to compare the Gibbs free energy of the Mpro-ligand bound and standard inhibitor bound complexes. The analysis revealed that the His-41, Cys145, Met49, and Leu27 amino acid residues were majorly responsible for the lower free energy of the complex. Drug likeness and physiochemical properties of the test compounds showed satisfactory results. Taken together, the study concludes that that the Isoquercetin and 10-Hydroxyaloin A phytochemical possess significant efficacy to bind SARS-Cov-2 Mpro active site. The study necessitates further in vitro and in vivo experimental validation of these lead phytochemicals to assess their anti-SARS-CoV-2 potential.

scholarly journals Retro Drug Design: From Target Properties to Molecular Structures

2021 ◽  
Author(s):  
Yuhong Wang ◽  
Sam Michael ◽  
Ruili Huang ◽  
Jinghua Zhao ◽  
Katlin Recabo ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Molecular Descriptor ◽  
Pharmaceutical Research ◽  
Monte Carlo Sampling ◽  
Molecular Structures ◽  
Descriptor System ◽  
Chemical Structures ◽  
Drug Molecules ◽  
Property Space

To generate drug molecules of desired properties with computational methods is the holy grail in pharmaceutical research. Here we describe an AI strategy, retro drug design, or RDD, to generate novel small molecule drugs from scratch to meet predefined requirements, including but not limited to biological activity against a drug target, and optimal range of physicochemical and ADMET properties. Traditional predictive models were first trained over experimental data for the target properties, using an atom typing based molecular descriptor system, ATP. Monte Carlo sampling algorithm was then utilized to find the solutions in the ATP space defined by the target properties, and the deep learning model of Seq2Seq was employed to decode molecular structures from the solutions. To test feasibility of the algorithm, we challenged RDD to generate novel drugs that can activate μ opioid receptor (MOR) and penetrate blood brain barrier (BBB). Starting from vectors of random numbers, RDD generated 180,000 chemical structures, of which 78% were chemically valid. About 42,000 (31%) of the valid structures fell into the property space defined by MOR activity and BBB permeability. Out of the 42,000 structures, only 267 chemicals were commercially available, indicating a high extent of novelty of the AI-generated compounds. We purchased and assayed 96 compounds, and 25 of which were found to be MOR agonists. These compounds also have excellent BBB scores. The results presented in this paper illustrate that RDD has potential to revolutionize the current drug discovery process and create novel structures with multiple desired properties, including biological functions and ADMET properties. Availability of an AI-enabled fast track in drug discovery is essential to cope with emergent public health threat, such as pandemic of COVID-19.

scholarly journals Molecular Dynamics Simulations of the Interaction of Mouse andTorpedoAcetylcholinesterase with Covalent Inhibitors Explain Their Differential Reactivity: Implications for Drug Design

2019 ◽  
Author(s):  
Nellore Bhanu Chandar ◽  
Irena Efremenko ◽  
Israel Silman ◽  
Jan M.L. Martin ◽  
Joel L. Sussman
Keyword(s):  
Molecular Dynamics ◽  
Drug Design ◽  
Molecular Dynamics Simulations ◽  
Active Site ◽  
Three Dimensional ◽  
Docking Studies ◽  
Covalent Modification ◽  
Phenylmethylsulfonyl Fluoride ◽  
Living Organisms ◽  
Dynamics Simulations

AbstractAlthough the three-dimensional structures of mouse andTorpedo californicaacetylcholinesterase are very similar, their responses to the covalent sulfonylating agents benzenesulfonyl fluoride and phenylmethylsulfonyl fluoride are qualitatively different. Both agents inhibit the mouse enzyme effectively by covalent modification of its active-site serine. In contrast, whereas theTorpedoenzyme is effectively inhibited by benzenesulfonyl fluoride, it is completely resistant to phenylmethylsulfonyl fluoride. A bottleneck midway down the active-site gorge in both enzymes restricts access of ligands to the active site at the bottom of the gorge. Molecular dynamics simulations revealed that the mouse enzyme is substantially more flexible than theTorpedoenzyme, suggesting that enhanced ‘breathing motions’ of the mouse enzyme relative to theTorpedoenzyme might explain why phenylmethylsulfonyl fluoride can reach the active site in mouse acetylcholinesterase, but not in theTorpedoenzyme. Accordingly, we performed docking of the two sulfonylating agents to the two enzymes, followed by molecular dynamics simulations. Whereas benzenesulfonyl fluoride closely approached the active-site serine in both mouse andTorpedoacetylcholinesterase in such simulations, phenylmethylsulfonyl fluoride was able to approach the active-site serine of mouse acetylcholinesterase - but remained trapped above the bottleneck in the case of theTorpedoenzyme. Our studies demonstrate that reliance on docking tools in drug design can produce misleading information. Docking studies should, therefore, also be complemented by molecular dynamics simulations in selection of lead compounds.Author summaryEnzymes are protein molecules that catalyze chemical reactions in living organisms, and are essential for their physiological functions. Proteins have well defined three-dimensional structures, but display flexibility; it is believed that this flexibility, known as their dynamics, plays a role in their function. Here we studied the neuronal enzyme acetylcholinesterase, which breaks down the neurotransmitter, acetylcholine. The active site of this enzyme is deeply buried, and accessed by a narrow gorge. A particular inhibitor, phenylmethylsulfonyl fluoride, is known to inhibit mouse acetylcholinesterase, but not that of the electric fish,Torpedo, even though their structures are very similar. A theoretical technique called molecular dynamics (MD) shows that the mouse enzyme is more flexible than theTorpedo enzyme. Furthermore, when the movement of the inhibitor down the gorge towards the active site is simulated using MD, the phenylmethylsulfonyl fluoride can reach the active site in the mouse enzyme, but not in theTorpedoenzyme, in which it remains trapped midway down the gorge. Our study emphasizes the importance of taking into account not only structure, but also dynamics, in designing drugs targeted towards proteins.

scholarly journals The Effect of ACE2 Inhibitor MLN-4760 on the Interaction of SARS-CoV-2 Spike Protein with Human ACE2: A Molecular Dynamics Study

2020 ◽  
Author(s):  
Babak Nami ◽  
Avrin Ghanaeian ◽  
Kasra Ghanaeian ◽  
Negin Nami
Keyword(s):  
Molecular Dynamics ◽  
Protein Interactions ◽  
Viral Entry ◽  
Active Site ◽  
Md Simulation ◽  
Inhibitory Effect ◽  
Major Effect ◽  
Spike Protein ◽  
Enzymatic Function ◽  
Hydrophobic Binding

<p>A previous study shows that an ACE2 enzymatic activity inhibitor efficiently blocks the interaction of SARS-CoV spike protein with human ACE2 and may be effective in preventing the coronavirus membrane fusion and entry to human cells. The report suggests that potent ACE2 inhibitors can be used to treat hypertension as well as for controlling SARS-CoV infection. We here studied the effect of a selective and highly potent ACE2 inhibitor (MLN-4760) on the interaction of the SARS-CoV-2 spike receptor-binding domain (RBD) with human ACE2 by molecular dynamics (MD) simulation. To this end, we docked the RBD of SARS-CoV-2 to the human native ACE2 and the ACE2 complexed with MLN-4760, and analyzed the dynamics, protein-protein and ligand-protein interactions of the complexes by MD simulation in a simulated biological condition for 100 ns. Analyzing crystallographic structures of SARS-CoV-2 and SARS-CoV RBDs in the complexes with human ACE2 showed that RBD of SARS-CoV-2 binds to ACE2 with a higher affinity than that of SARS-CoV. Results also revealed that MLN-4760 binds to ACE2 at the enzymatic active site with a high affinity and significantly alters the ACE2 protein conformation. MLN-4760 also changes the binding site and the residues involved in hydrogen and hydrophobic binding between RBD and ACE2, however, it had no major effect on the binding affinity of the interaction between RDB and ACE2. Interestingly, binding RBD to the ACE2 complexed with MLN-4760 abrogated the inhibitory effect of MLN-4760 and rescued the conformation of the ACE2 enzymatic site by reforming the closed conformation to the open native conformation. This was due to the disassociation of MLN-4760 from the enzymatic active site of the ACE2 in the result of RBD binding. Overall, these results show that MLN-4760 does neither block nor increase the binding of SARS-CoV-2 spike RBD to human ACE2 and probably had no effect on the viral entry. However, binding the spike protein to ACE2 can rescue the enzymatic function of ACE2 from its inhibitor.</p>

scholarly journals Curvature induction and sensing of the F-BAR protein Pacsin1 on lipid membranes via molecular dynamics simulations

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Md. Iqbal Mahmood ◽  
Hiroshi Noguchi ◽  
Kei-ichi Okazaki
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Lipid Membranes ◽  
Lipid Membrane ◽  
Complex Structure ◽  
Membrane Curvature ◽  
Coarse Grained ◽  
Lateral Interaction ◽  
Bar Domain ◽  
Dynamics Simulations

Abstract F-Bin/Amphiphysin/Rvs (F-BAR) domain proteins play essential roles in biological processes that involve membrane remodelling, such as endocytosis and exocytosis. It has been shown that such proteins transform the lipid membrane into tubes. Notably, Pacsin1 from the Pacsin/Syndapin subfamily has the ability to transform the membrane into various morphologies: striated tubes, featureless wide and thin tubes, and pearling vesicles. The molecular mechanism of this interesting ability remains elusive. In this study, we performed all-atom (AA) and coarse-grained (CG) molecular dynamics simulations to investigate the curvature induction and sensing mechanisms of Pacsin1 on a membrane. From AA simulations, we show that Pacsin1 has internal structural flexibility. In CG simulations with parameters tuned from the AA simulations, spontaneous assembly of two Pacsin1 dimers through lateral interaction is observed. Based on the complex structure, we show that the regularly assembled Pacsin1 dimers bend a tensionless membrane. We also show that a single Pacsin1 dimer senses the membrane curvature, binding to a buckled membrane with a preferred curvature. These results provide molecular insights into polymorphic membrane remodelling.

scholarly journals Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5304
Author(s):  
Mohammad G. Al-Thiabat ◽  
Amirah Mohd Gazzali ◽  
Noratiqah Mohtar ◽  
Vikneswaran Murugaiyah ◽  
Ezatul Ezleen Kamarulzaman ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Folic Acid ◽  
Root Mean Square ◽  
Active Site ◽  
Md Simulation ◽  
Binding Free Energy ◽  
Cancer Drug ◽  
Radius Of Gyration ◽  
Mean Square ◽  
The Stability

Drug targeting is a progressive area of research with folate receptor alpha (FRα) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FRα active site provides a basis for recognition of FRα. In this study, FA was conjugated to beta-cyclodextrin (βCD) and subjected to in silico analysis (molecular docking and molecular dynamics (MD) simulation (100 ns)) to investigate the affinity and stability for the conjugated system compared to unconjugated and apo systems (ligand free). Docking studies revealed that the conjugated FA bound into the active site of FRα with a docking score (free binding energy < −15 kcal/mol), with a similar binding pose to that of unconjugated FA. Subsequent analyses from molecular dynamics (MD) simulations, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) demonstrated that FA and FA–βCDs created more dynamically stable systems with FRα than the apo-FRα system. All systems reached equilibrium with stable RMSD values ranging from 1.9–2.4 Å and the average residual fluctuation values of the FRα backbone atoms for all residues (except for terminal residues ARG8, THR9, THR214, and LEU215) were less than 2.1 Å with a consistent Rg value of around 16.8 Å throughout the MD simulation time (0–100 ns). The conjugation with βCD improved the stability and decreased the mobility of all the residues (except residues 149–151) compared to FA–FRα and apo-FRα systems. Further analysis of H-bonds, binding free energy (MM-PBSA), and per residue decomposition energy revealed that besides APS81, residues HIS20, TRP102, HIS135, TRP138, TRP140, and TRP171 were shown to have more favourable energy contributions in the holo systems than in the apo-FRα system, and these residues might have a direct role in increasing the stability of holo systems.

scholarly journals Structure-based docking, pharmacokinetic evaluation, and molecular dynamics-guided evaluation of traditional formulation against SARS-CoV-2 spike protein receptor bind domain and ACE2 receptor complex

2021 ◽  
Author(s):  
B. Harish kumar ◽  
Suman Manandhar ◽  
Chetan H. Mehta ◽  
Usha Y. Nayak ◽  
K. Sreedhara Ranganath Pai
Keyword(s):  
Molecular Dynamics ◽  
Chlorogenic Acid ◽  
Viral Entry ◽  
Md Simulation ◽  
Binding Potential ◽  
Drug Molecules ◽  
Protein Receptor ◽  
Glide Docking ◽  
The Many

AbstractThere is an urgent need for reliable cure and preventive measures in this hour of the outbreak of SARS-CoV-2. Siddha- and Ayurvedic-based classical formulations have antiviral properties and great potential therapeutic choice in this pandemic situation. In the current study, in silico-based analysis for the binding potential of phytoconstituents from the classical formulations suggested by the Ministry of Ayush (Kabasura Kudineer, Shwas Kuthar Rasa with Kantakari and pippali churna, Talisadi churna) to the interface domain of the SARS-CoV-2 receptor-binding domain and angiotensin-converting enzyme 2 was performed. Maestro software from Schrodinger and tools like Glide Docking, induced fit docking, MM-GBSA, molecular dynamics (MD) simulation, and thermal MM-GBSA was used to analyze the binding of protein PDB ID:6VW1 and the selected 133 ligands in comparison with drug molecules like favipiravir and ribavirin. QikProp-based ADMET evaluation of all the phytoconstituents found them nontoxic and with drug-like properties. Selection of top ten ligands was made based on docking score for further MM-GBSA analysis. After performing IFD of top five molecules iso-chlorogenic acid, taxiphyllin, vasicine, catechin and caffeic acid, MD simulation and thermal MM-GBSA were done. Iso-chlorogenic acid had formed more stable interaction with key residue among all phytoconstituents. Computational-based study has highlighted the potential of the many constituents of traditional medicine to interact with the SARS-CoV-2 RBD and ACE2, which might stop the viral entry into the cell. However, in vivo experiments and clinical trials are necessary for supporting this claim.

scholarly journals The Effect of ACE2 Inhibitor MLN-4760 on the Interaction of SARS-CoV-2 Spike Protein with Human ACE2: A Molecular Dynamics Study

2020 ◽  
Author(s):  
Babak Nami ◽  
Avrin Ghanaeian ◽  
Kasra Ghanaeian ◽  
Negin Nami
Keyword(s):  
Molecular Dynamics ◽  
Protein Interactions ◽  
Viral Entry ◽  
Active Site ◽  
Md Simulation ◽  
Inhibitory Effect ◽  
Major Effect ◽  
Spike Protein ◽  
Enzymatic Function ◽  
Hydrophobic Binding

<p>A previous study shows that an ACE2 enzymatic activity inhibitor efficiently blocks the interaction of SARS-CoV spike protein with human ACE2 and may be effective in preventing the coronavirus membrane fusion and entry to human cells. The report suggests that potent ACE2 inhibitors can be used to treat hypertension as well as for controlling SARS-CoV infection. We here studied the effect of a selective and highly potent ACE2 inhibitor (MLN-4760) on the interaction of the SARS-CoV-2 spike receptor-binding domain (RBD) with human ACE2 by molecular dynamics (MD) simulation. To this end, we docked the RBD of SARS-CoV-2 to the human native ACE2 and the ACE2 complexed with MLN-4760, and analyzed the dynamics, protein-protein and ligand-protein interactions of the complexes by MD simulation in a simulated biological condition for 100 ns. Analyzing crystallographic structures of SARS-CoV-2 and SARS-CoV RBDs in the complexes with human ACE2 showed that RBD of SARS-CoV-2 binds to ACE2 with a higher affinity than that of SARS-CoV. Results also revealed that MLN-4760 binds to ACE2 at the enzymatic active site with a high affinity and significantly alters the ACE2 protein conformation. MLN-4760 also changes the binding site and the residues involved in hydrogen and hydrophobic binding between RBD and ACE2, however, it had no major effect on the binding affinity of the interaction between RDB and ACE2. Interestingly, binding RBD to the ACE2 complexed with MLN-4760 abrogated the inhibitory effect of MLN-4760 and rescued the conformation of the ACE2 enzymatic site by reforming the closed conformation to the open native conformation. This was due to the disassociation of MLN-4760 from the enzymatic active site of the ACE2 in the result of RBD binding. Overall, these results show that MLN-4760 does neither block nor increase the binding of SARS-CoV-2 spike RBD to human ACE2 and probably had no effect on the viral entry. However, binding the spike protein to ACE2 can rescue the enzymatic function of ACE2 from its inhibitor.</p>

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