Molecular modeling studies on series of Btk inhibitors using docking, structure-based 3D-QSAR and molecular dynamics simulation: a combined approach

Pavithra K. Balasubramanian,Seung Joo Cho,Anand Balupuri 대한약학회 2016 Archives of Pharmacal Research Vol.39 No.3

Bruton tyrosine kinase (Btk) is a non-receptor tyrosine kinase. It is a crucial component in BCR pathway and expressed only in hematopoietic cells except T cells and Natural killer cells. BTK is a promising target because of its involvement in signaling pathways and B cell diseases such as autoimmune disorders and lymphoma. In this work, a combined molecular modeling study of molecular docking, 3D-QSAR and molecular dynamic (MD) simulation were performed on a series of 2,5-diaminopyrimidine compounds as inhibitors targeting Btk kinase to understand the interaction and key residues involved in the inhibition. A structure based CoMFA (q2 = 0.675, NOC = 5, r2 = 0.961) and COMSIA (q2 = 0.704, NOC = 6, r2 = 0.962) models were developed from the conformation obtained by docking. The developed models were subjected to various validation techniques such as leave-five-out, external test set, bootstrapping, progressive sampling and rm2 metrics and found to have a good predictive ability in both internal and external validation. Our docking results showed the important residues that interacts in the active site residues in inhibition of Btk kinase. Furthermore, molecular dynamics simulation was employed to study the stability of the docked conformation and to investigate the binding interactions in detail. The MD simulation analyses identified several important hydrogen bonds with Btk, including the gatekeeper residue Thr474 and Met477 at the hinge region. Hydrogen bond with active site residues Leu408 and Arg525 were also recognized. A good correlation between the MD results, docking studies and the contour map analysis are observed. This indicates that the developed models are reliable. Our results from this study can provide insights in the designing and development of more potent Btk kinase inhibitors.

Molecular Dynamics Simulation of Charged Liquid/Vapour Interface

( T. Funakawa ),( W. Balachandran ) 한국액체미립화학회 2005 한국액체미립화학회 학술강연회 논문집 Vol.2005 No.-

The paper discusses the instability mechanism of charged liquid/vapour interface using 3D Molecular Dynamics (MD) simulation. The equilibrium liquid/vapour interface was created in a rectangular simulation box, in which the periodical boundary condition is applied in all directions. The surface tension, the normal pressure, the bulk viscosity, and the shear viscosity were calculated respectively in both charged and uncharged conditions in order to determine the cause of the instability. The instability mechanisms were analyzed by comparison of the charged and uncharged simulation results. Ethane molecule was chosen as a sample fluid in this study. The Electron Bubble (EB), which is known as the main charge carrier of insulating liquids, represents an ion producing the electric field in the liquid/vapor interface. The 2CLJ potential was used for the calculation of the molecular interactions. The Coulomb and the polarization potentials were used to consider the EB effects on the molecules. The separation distance between methyl sites in the ethane molecule was constrained to be constant by the Rattle Algorithm. The reduction of the surface tension was confirmed in the condition when the liquid/vapour interface was charged. The reduction phenomenon appears to be induced by the shear stress increasing in the liquid/vapour interface due to the molecular aggregation effects by the EBs in the liquid phase.

Accelerating Molecular Dynamics Simulation Using Graphics Processing Unit

Hun Joo Myung,Sik Lee,오광진,Ryuji Sakamaki,Tetsu Narumi,Kenji Yasuoka 대한화학회 2010 Bulletin of the Korean Chemical Society Vol.31 No.12

We have developed CUDA-enabled version of a general purpose molecular dynamics simulation code for GPU. Implementation details including parallelization scheme and performance optimization are described. Here we have focuse on the non-bonded force calculation because it is most time consuming part in molecular dynamics simulation. Timing results using CUDA-enabled and CPU versions were obtained and compared for a biomolecular system containing 23558 atoms. CUDA-enabled versions were found to be faster than CPU version. This suggests that GPU could be a useful hardware for molecular dynamics simulation.

Accelerating Molecular Dynamics Simulation Using Graphics Processing Unit

Myung, Hun-Joo,Sakamaki, Ryuji,Oh, Kwang-Jin,Narumi, Tetsu,Yasuoka, Kenji,Lee, Sik Korean Chemical Society 2010 Bulletin of the Korean Chemical Society Vol.31 No.12

We have developed CUDA-enabled version of a general purpose molecular dynamics simulation code for GPU. Implementation details including parallelization scheme and performance optimization are described. Here we have focused on the non-bonded force calculation because it is most time consuming part in molecular dynamics simulation. Timing results using CUDA-enabled and CPU versions were obtained and compared for a biomolecular system containing 23558 atoms. CUDA-enabled versions were found to be faster than CPU version. This suggests that GPU could be a useful hardware for molecular dynamics simulation.

Effects of density on flow in a nano channel using a molecular-continuum hybrid method

Kim, Youngjin,Jeong, Myunggeun,Zhou, Wenjing,Tao, Wen Quan,Ambrosia, Matthew Stanley,Ha, Man Yeong Elsevier 2017 Computers & fluids Vol.156 No.-

<P><B>Abstract</B></P> <P>A molecular-continuum hybrid method was developed to simulate micro- and nano-scale fluid flows that cannot be predicted using continuum fluidics. Molecular dynamics simulation was used near stationary solid surfaces, and Navier-Stokes equations were used in other regions. We carried out Couette flow simulation using this hybrid method and validated the results by comparing them with the analytical solution. We also studied the dependence of the velocity slip and slip length on the surface energy, liquid density, and roughness for a liquid channel flow with and without nano-structures on the solid surface. The behavior of the liquid near the solid wall changed with the surface energy as well as the liquid density. The variation of the velocity slip and slip length according to the surface energy also depended on the liquid density as well as the surface roughness. We compared the required computational time obtained from the molecular-continuum hybrid method with that obtained from full molecular dynamics simulation under the same computational condition, giving much shorter computational time for the case using the molecular-continuum hybrid method than that for full molecular dynamics simulation.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The velocity slip and slip length decrease with increasing the surface energy. </LI> <LI> The locking boundary condition is enhanced with the structure. </LI> <LI> The trends of <I>u<SUB>s</SUB> </I> and <I>L<SUB>s</SUB> </I> at each liquid density are changed on the smooth surface. </LI> <LI> The trends at each liquid density differ between the rough and smooth surface. </LI> </UL> </P>

Molecular dynamics simulation of carbon molecular sieve preparation for air separation

Elham Yaghoobpour,ALI AHMADPOUR,Nafiseh Farhadian,Mojtaba Shariaty-Niassar 한국화학공학회 2015 Korean Journal of Chemical Engineering Vol.32 No.3

Carbon deposition process on activated carbon (AC) in order to produce carbon molecular sieve (CMS)was simulated using molecular dynamics simulation. The proposed activated carbon for simulation includes microporeswith different characteristic diameters and lengths. Three different temperatures of 773 K, 973 K, and 1,273 K wereselected to investigate the optimum deposition temperature. Simulation results show that the carbon deposition processat 973 K creates the best adsorbent structure. While at lower temperature some micropore openings are blockedwith carbon atoms, at higher temperature the number of deposited carbons on the micropores does not change significantly. Also, carbon deposition process confirms the pseudo-second-order kinetic model with an endothermic behavior. To evaluate the sieving property of adsorbent products, nitrogen and oxygen adsorption on the initial and finaladsorbent products are examined. Results show that there is not any considerable difference between the equilibriumadsorption amounts of nitrogen and oxygen on the initial and final adsorbents especially at low pressure (P<10 atm). Although, adsorption kinetics curves of these gases change significantly after the carbon deposition process in comparisonwith the initial sample. These observations indicate that the final adsorbent has high selectivity towards oxygencompared with the nitrogen, so it can be called a carbon molecular sieve. All simulated results are in good agreementwith experiments.

A comprehensive molecular dynamics study of a single polystyrene chain in a good solvent

Sajad Rasouli,Mohammad Reza Moghbeli,Sousa Javan Nikkhah 한국물리학회 2018 Current Applied Physics Vol.18 No.1

In this study, molecular characteristics of polystyrene (PS) was calculated measuring its dilute-solution properties in toluene at 288.15 K via molecular dynamics (MD) simulations. The solution models consisted of PS chains with different number of repeating units all of which were in a dilute regime. In order to investigate the compatibility between the polymer and the solvent molecules, interaction energy and Flory-Huggins (FH) interaction parameter were estimated. The simulation results indicate that increasing the chain repeating units enhanced the interaction between the solute and the solvent. Additionally, the chain dimensions were evaluated calculating the radius of gyration (Rg) and end-to-end distance, r0. To determine the dynamic behavior of the chains in the solutions, mean square displacement (MSD) and diffusivity coefficient were calculated. The simulation results indicated that the chain rigidity at low molecular weight and chain flexibility with increasing the molecular weight influenced chains dynamic behavior and diffusivity. Moreover, radial distribution function (RDF) illustrated the effect of steric hindrance of the chains in dilute solution on capturing the solvent molecules. In addition, solution viscosity was calculated by performing non-equilibrium molecular dynamics simulation (NEMD). The obtained results of chain characteristics and viscosity showed a good agreement with experimental results published previously. This agreement confirms the accuracy of the applied simulation method to characterize the dilute solutions and the chains characteristics.

토도로카이트 내 Mg²⁺ 배위구조에 대한 고전분자동력학 연구

김주혁 ( Juhyeok Kim ),이진용 ( Jin-yong Lee ),권기덕 ( Kideok D. Kwon ) 한국광물학회 2019 광물과 암석 (J.Miner.Soc.Korea) Vol.32 No.3

토도로카이트(todorokite)는 3 × 3 망간 팔면체로 이루어진 상대적으로 큰 나노공극(nanopore)을 가지는 터널구조의 산화망간광물로 나노공극에 다양한 양이온 함유가 가능하기 때문에 금속이온 거동에 큰 역할을 할 수 있다. 주로 결정도가 낮고 다른 산화망간광물들과 함께 집합체로 발견되어 나노공극 내부 양이온의 배위(coordination)구조는 실험만으로 여전히 규명하기 매우 어렵다. 이번 논문에서는 고전분자동력학(classical molecular dynamics, MD) 시뮬레이션을 이용하여 토도로카이트 터널에 함유된 Mg²⁺ 이온의 배위구조에 대한 연구결과를 처음으로 소개한다. 기존 실험에서는 토도로카이트 내부에 함유된 Mg²⁺가 공극의 중앙에 우세하게 자리한다고 알려져 있다. MD 시뮬레이션 결과, Mg²⁺ 이온의 약 60 %가 나노공극의 중앙에 위치하지만, 약 40 %의 Mg²⁺는 광물의 표면에 해당하는 공극의 코너에 위치하였다. 공극 중앙의 Mg²⁺는 수용액에서처럼 물 분자와 6배위수를 보였다. 공극 코너의 Mg²⁺ 역시 6배위수를 보였는데, 물 분자 이외에도 망간 팔면체 표면 산소와 배위를 보였다. Mg²⁺ 이온의 동적 거동을 파악하기 위해 계산한 평균 제곱 변위(mean squared displacement) 결과에서는, 수용액 벌크(bulk) 상태에서 갖는 물 분자와 양이온의 동적 성질이 토도로카이트 1D 나노공극에서는 유지되지 못하고 잃어버리는 것을 확인할 수 있었다. Todorokite, a tunnel-structured manganese oxide, can contain cations within the relatively large nanopores created by the 3 × 3 Mn octahedra. Because todorokite is poorly crystalline and found as aggregates mixed with other phases of Mn oxides in nature, the coordination structure of cations in the nanopores is challenging to fully characterize in experiment. In the current article, we report the atomistic coordination structures of Mg²⁺ ions in todorokite tunnel nanopores using the classical molecular dynamics (MD) simulations. In experiment, Mg²⁺ is known to occupy the center of the nanopores. In our MD simulations, 60 % of Mg²⁺ ions were located at the center of the nanopores; 40 % of the ions were found at the corners. All Mg²⁺ located at the center formed the six-fold coordination with water molecules, just as the ion in bulk aqueous solution. Mg²⁺ ions at the corners also formed the six-fold coordination with not only water molecules but also Mn octahedral surface oxygens. The mean squared displacements were calculated to examine the dynamic features of Mg²⁺ ions in the one-dimensional (1D) nanopores. Our MD simulations indicate that the dynamic features of water molecules and the cations observed in bulk aqueous solution are lost in the 1D nanopores of todorokite.

Qualitative study of nanocluster positioning process: Planar molecular dynamics simulations

S.H. Mahboobi,A. Meghdari,N. Jalili,F. Amiri 한국물리학회 2009 Current Applied Physics Vol.9 No.5

One of the key factors in the assembly of nanoclusters is the precise positioning of them by a manipulation system. Currently the size of clusters used as building blocks is shrinking down to a few nanometers. In such cases, the particle nature of matter plays an important role in the manipulator/cluster/substrate interactions. Having a deeper insight to the aforementioned nano-scale interactions is crucial for prediction and understanding of the behavior of nanoclusters during the positioning process. In the present research, 2D molecular dynamics simulations have been used to investigate such behaviors. Performing planar simulations can provide a fairly acceptable qualitative tool for our purpose while the computation time is greatly reduced in comparison to 3D simulations. The system consists of a tip, cluster and substrate. The focus of the present research is on ultra-fine metallic nanoclusters. To perform this research, Nose–Hoover dynamics and Sutton–Chen interatomic potential will be used to investigate the behavior of the above system which is made from different transition metals. The effects of material type, tip form and manipulation strategy on the success of the process have been investigated by planar molecular dynamics. Such qualitative simulation studies can evaluate the chance of success of a certain nanopositioning scenario regarding different working conditions before consuming large-scale computation time or high experimental expenses.

Computational Modeling of Novel Phosphoinositol-3-kinase γ Inhibitors Using Molecular Docking, Molecular Dynamics, and 3D-QSAR

Suparna Ghosh,Seketoulie Keretsu,Seung Joo Cho 대한화학회 2021 Bulletin of the Korean Chemical Society Vol.42 No.8

Phosphoinositol-3-kinase ? (PI3K?) is a member of the class-IB PI3K superfamily and plays a significant role in G-protein-coupled receptor mediated cell signaling. Recent studies have suggested that elevated expression of PI3K? in tumor-associated macrophages strongly influences immune suppression and tumor growth. Due to the presence of many isoforms of PI3K, the selective inhibition of PI3K? remains challenging. Therefore, it is necessary to design more potent inhibitors against PI3K? for cancer treatment. In this study, we have reported the critical interactions of isoindolinone-based inhibitors with PI3K? by docking and molecular dynamics simulations. The binding free energy of the receptor-ligand complex was calculated using molecular mechanics/Poison-Boltzmann surface area approach. We have performed the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA) to determine the structure?activity relationship of the inhibitors. The CoMFA (q2 = 0.681 and r2 = 0.968) and CoMSIA (q2 = 0.665 and r2 = 0.982) models showed reasonable predictive ability. Thereafter, the contour maps derived from CoMFA and CoMSIA were used to design several new compounds, among which, the compound D04 showed high predicted activity values. The designed compound was subjected to absorption-distribution-metabolism-excretion/toxicity prediction and synthetic accessibility analyses. Our results could provide theoretical guidance for the future development of new PI3K? inhibitors.