Homology modeling and virtual screening approaches to identify potent inhibitors of slingshot phosphatase 1

Although slingshot phosphatase 1 (SSH1) proved to be a promising target for the development of therapeutics for the treatment of vascular diseases and cancers, no small-molecule inhibitor has been reported so far. We have been able to identify eight novel inhibitors of SSH1 through the computer-aided drug design protocol involving homology modeling of SSH1 structure, virtual screening of a large chemical library with docking simulations, and in vitro enzyme assays. The identified inhibitors revealed high potencies with the associated IC₅₀ values ranging from 2.8 to 12.7 μM and were also screened for having desirable physicochemical properties as a drug candidate. Therefore, they deserve consideration for further development by structure–activity relationship studies to optimize the inhibitory activities. Structural features relevant to the stabilization of the inhibitors in the active site of SSH1 are discussed in detail.     

Molecular modeling study of CP-690550 derivatives as JAK3 kinase inhibitors through combined 3D-QSAR,molecular docking,and dynamics simulation techniques

To develop more potent JAK3 kinase inhibitors, a series of CP-690550 derivatives were investigated using combined molecular modeling techniques, such as 3D-QSAR, molecular docking and molecular dynamics (MD). The leave-one-out correlation (q²) and non-cross-validated correlation coefficient (r²) of the best CoMFA model are 0.715 and 0.992, respectively. The q² and r² values of the best CoMSIA model are 0.739 and 0.995, respectively. The steric, electrostatic, and hydrophobic fields played important roles in determining the inhibitory activity of CP-690550 derivatives. Some new JAK3 kinase inhibitors were designed. Some of them have better inhibitory activity than the most potent Tofacitinib (CP-690550). Molecular docking was used to identify some key amino acid residues at the active site of JAK3 protein. 10 ns MD simulations were successfully performed to confirm the detailed binding mode and validate the rationality of docking results. The calculation of the binding free energies by MMPBSA method gives a good correlation with the predicted biological activity. To our knowledge, this is the first report on MD simulations and free energy calculations for this series of compounds. The combination results of this study will be valuable for the development of potent and novel JAK3 kinase inhibitors.     

Modeling aided design of potent glycogen phosphorylase inhibitors

Molecular modeling has been used to assist in the development of a novel series of potent glycogen phosphorylase inhibitors based on a phenyl diacid lead, compound 1. In the absence of suitable competitive binding assays, compound 1 was predicted to bind at the AMP allosteric site based on superposition onto known inhibitors which bind at different sites in the enzyme and analyses of the surrounding protein environment associated with these distinct sites. Possible docking modes of compound 1 at the AMP allosteric site were further explored using the crystal structure of rabbit muscle glycogen phosphorylase complexed with a Bayer diacid compound W1807 (PDB entry 3AMV). Compound 1 was predicted to interact with positively charged arginines at the AMP allosteric site in the docking model. Characterization of the binding pocket by a grid-based surface calculation of the docking model revealed a large unfilled hydrophobic region near the central phenyl ring, suggesting that compounds with larger hydrophobic groups in this region would improve binding. A series of naphthyl diacid compounds were designed and synthesized to access this hydrophobic cleft, and showed significantly improved potency.     

Ubiquitin: Molecular modeling and simulations

The synthesis and destruction of proteins are imperative for maintaining their cellular homeostasis. In the 1970s, Aaron Ciechanover, Avram Hershko, and Irwin Rose discovered that certain proteins are tagged by ubiquitin before degradation, a discovery that awarded them the 2004 Nobel Prize in Chemistry. Compelling data gathered during the last several decades show that ubiquitin plays a vital role not only in protein degradation but also in many cellular functions including DNA repair processes, cell cycle regulation, cell growth, immune system functionality, hormone-mediated signaling in plants, vesicular trafficking pathways, regulation of histone modification and viral budding. Due to the involvement of ubiquitin in such a large number of diverse cellular processes, flaws and impairments in the ubiquitin system were found to be linked to cancer, neurodegenerative diseases, genetic disorders, and immunological disorders. Hence, deciphering the dynamics and complexity of the ubiquitin system is of significant importance. In addition to experimental techniques, computational methodologies have been gaining increasing influence in protein research and are used to uncover the structure, stability, folding, mechanism of action and interactions of proteins. Notably, molecular modeling and molecular dynamics simulations have become powerful tools that bridge the gap between structure and function while providing dynamic insights and illustrating essential mechanistic characteristics. In this study, we present an overview of molecular modeling and simulations of ubiquitin and the ubiquitin system, evaluate the status of the field, and offer our perspective on future progress in this area of research.     

A priori molecular descriptors in QSAR: a case of HIV-1 protease inhibitors. II. Molecular graphics and modeling

Molecular graphics and modeling methods illustrated the chemical background of the a priori approach from part I, and visualized steric and electronic enzyme-inhibitor relationships at qualitative and quantitative level for 34 and its derivatives. The enzyme-inhibitor electron density overlap occurs at 1.5–5.5 Å cut-off distance, beyond van der Waals radii. Derivatives of 34 exhibit linear relationships between biological activity, molecular size and number of intermolecular interactions.     

Molecular modeling optimization of anticoagulant pyridine derivatives

Intravascular clotting remains a major health problem in the United States, the most prominent being deep vein thrombosis, pulmonary embolism and thromboembolic stroke. Previous reports on the use of pyridine derivatives in cardiovascular drug development encourage us to pursue new types of compounds based on a pyridine scaffold. Eleven pyridine derivatives (oximes, semicarbazones, N-oxides) previously synthesized in our laboratories were tested as anticoagulants on pooled normal plasma using the prothrombin time (PT) protocol. The best anticoagulant within the oxime series was compound AF4, within the oxime N-oxide series was compound AF4-N-oxide, and within the semicarbazone series, compound MD1-30Y. We also used a molecular modeling approach to guide our efforts, and found that there was good correlation between coagulation data and computational energy scores. Molecular docking was performed to target the active site of thrombin with the DOCK v5.2 package. The results of molecular modeling indicate that improvement in anticoagulant activities can be expected by functionalization at the three-position of the pyridine ring and by N-oxide formation. Results reported here prove the suitability of DOCK in the lead optimization process.     

活性肽搜寻与蛋白模拟水解数据库的建立

利用Microsoft Office XP中的Access XP数据库软件建立3个数据库系统,蛋白质数据库包含小麦面筋、大米、玉米等常见食物蛋白质序列23739条,活性肽数据库包含ACE抑制肽、免疫肽、阿片肽等生物活性肽序列1396条,以及常见的蛋白质水解酶信息。数据库与编制的“生物活性肽搜寻与酶解模拟系统”程序配合,实现单条、多条活性肽序列在蛋白质中批量搜寻,并找出活性肽含量的链长百分比,活性肽在蛋白质中的位置和前后氨基酸的种类,实现肽的活性不完全归纳预测活性,实现蛋白质用单酶或者复酶的模拟水解并标出水解产物中活性肽及其功能。     

Convergence of a modified algorithm of fast probabilistic modeling

The convergence of fast probabilistic modeling algorithms (G-algorithms) is analyzed. A G-algorithm is modified based on a new probabilistic approach, used to reject points in the neighborhood of the current solution. A theoretically justified estimate of the rate of convergence, independent of the initial approximation, is obtained for this modification. A computational experiment is conducted to compare the performance of the modified G-algorithm with that of the classical one. __________ Translated from Kibernetika i Sistemnyi Analiz, No. 1, pp. 173–179, January–February 2008.     

Conformational analysis and docking study of potent factor XIIIa inhibitors having a cyclopropenone ring

A conformational analysis and docking study of potent factor XIIIa inhibitors having a cyclopropenone ring were carried out in an attempt to obtain structural insight into the inhibition mechanism. First, stable conformers of the inhibitors alone were obtained from the conformational analysis by systematic search and molecular dynamics. Next, a binding form model of factor XIIIa was built based on an X-ray crystal structure of the enzyme. Finally, the docking study of the inhibitors into the model’s binding site was performed. From the resulting stable complex structures, it was found that the cyclopropenone ring fits the active site located at the base of the binding cavity with high complementarity. The carbonyl oxygen of the cyclopropenone ring formed a hydrogen bond to the indole NH group of Trp279 and the terminal carbon atom of the reactive C=C double bond was in close proximity to the sulfur atom of the catalytic residue, Cys314. This binding mode suggests a possible inhibition mechanism, whereby the cysteine residue reacts with the cyclopropenone ring of the inhibitor, forming an enzyme-ligand adduct. In addition, the higher interaction energies between factor XIIIa and the inhibitors alluded to the probable binding sites of the ligand side chain.     

Dynamic modeling and nonlinear tracking control of a novel modified quadrotor

In this article, a nonlinear tracking controller is designed based on Lyapunov stability for a novel aerial robot. The proposed 6‐rotor configuration improves stability and payload lifting capacity of the robot compared with conventional quadrotors while avoiding further complexities in the robot dynamics and steering principles. The dynamical model of the robot is derived using Newton‐Euler method. The model represents a nonlinear, coupled, and underactuated system. The proposed control strategy includes 2 main parts: an attitude controller and a position controller. Both the attitude and position controls are Lyapunov‐based nonlinear tracking controllers that guarantee the asymptotic convergence of the states' tracking errors to zero. Simulation results are presented to illustrate appropriate performance of the closed‐loop system in terms of position/attitude tracking even in the presence of wind disturbance.     

Design,closed-form modeling and analysis of SU-8 based electrothermal microgripper for biomedical applications

Microsystem Technologies - This paper presents design analysis of an SU-8 based 2-DoF electrothermal microgripper by developing a closed-form analytical model. The analytical model considers both...     

Identification of potent urease inhibitors via ligand- and structure-based virtual screening and in vitro assays

A pharmacophore model was developed based on three structurally diverse urease inhibitors by using the GASP program. This model comprises the positions and tolerance for two acceptor atoms (AA1 and AA2), one donor atom (DA1), and one hydrophobic center (HYP1). This derived phamacophore model was employed to screen an in-house database of organic compounds. Hits obtained were evaluated by molecular docking using GOLD software. On the basis of ligand- and structural-based predictions, an in vitro testing of short-listed compounds was conducted and a novel class of urease inhibitors (2-aminothiophines) was identified. The potent in vitro activity and selectivity of these compounds, along with their non-toxic nature against the plant cells indicated that they can serve as leads for solving urease-associated health and agriculture problems.     

自组装二十烷二羰基二-L-谷氨酸纳米管的分子模拟

为了洞察自组装二十烷二羰基二-L-谷氨酸(Eicosanedioyl—di—L—glutamic acid)EDGA球形螺旋纳米管微观结构，我们在大型计算机工作站SGI3800上，利用CERIUS2分子模拟软件，进行了计算机分子模拟。首先，根据EDGA分子在纳米管壁中的受力情况，确定了相当于二维周期边界条件的三维周期边界模型，由分子动力学构象搜索法寻找低能量的分子构象，进而运用分子力学、分子动力学交替进行的退火算法对EDGA单层膜聚集体进行模拟计算；结果得到分子两端基谷氨酸的构象不同的最低能量的分子构象，和螺旋与弯曲两种趋势同时存在的EDGA单层膜聚集体。模拟结果可以合理地描述自组装二十烷二羰基二-L-谷氨酸球形螺旋纳米管的一些结构特征。     

Molecular modeling of enzyme attachment on AFM probes

The immobilization of enzymes on atomic force microscope tip (AFM tip) surface is a crucial step in the development of nanobiosensors to be used in detection process. In this work, an atomistic modeling of the attachment of the acetyl coenzyme A carboxylase (ACC enzyme) on a functionalized AFM tip surface is proposed. Using electrostatic considerations, suitable enzyme–surface orientations with the active sites of the ACC enzyme available for interactions with bulk molecules were found. A 50 ns molecular dynamics trajectory in aqueous solution was obtained and surface contact area, hydrogen bonding and protein stability were analyzed. The enzyme–surface model proposed here with minor adjustment can be applied to study antigen–antibody interactions as well as enzyme immobilization on silica for chromatography applications.     

Molecular dynamics simulations for selection of kinetic hydrate inhibitors

Natural gas hydrates are ice-like structures composed of water and gas molecules that have long been a problem in petroleum industry. Heavy cost of alcohol and glycol injection has spurred an interest in called ‘kinetic inhibitors’ able to slow down the hydrate formation rather than prevent it. Since it is not possible to compare directly the macroscopic effects of different inhibitors on the kinetics of hydrate formation in computer experiments, a scheme capable of culling the list of candidates for experimental testing was proposed earlier [B. Kvamme, G. Huseby, O.K. Førrisdahl, Molecular dynamics simulations of PVP kinetic inhibitor in liquid water and hydrate/liquid water systems, Mol. Phys. 90 (1997) 979–991]. Molecular dynamics simulations were implemented to test several kinetic inhibitors in a multiphase water–hydrate system with rigid hydrate interface. In addition, a long-scale run was implemented for a system where the hydrate was free to melt and reform. Our conclusion that PVCap will outperform PVP as a kinetic hydrate inhibitor is supported by experimental data. We demonstrate that numerical experiments can be a valuable tool for selecting kinetic inhibitors as well as provide insight into mechanisms of kinetic inhibition and hydrate melting and reformation.     

Molecular modeling, docking and ADMET studies applied to the design of a novel hybrid for treatment of Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia in adults, which is characterized by senile plaquets and cholinergic deficit as the disease progresses. Improvement of cholinergic neurotransmission is the basis of some drugs currently used in the treatment of AD. It is achieved by acetylcholinesterase (AChE) inhibition, the enzyme responsible for acetylcholine hydrolysis. Molecular modeling techniques were of utmost importance to design a new pharmaceutical against Alzheimer's disease, with potential inhibitory activity over AChE, since the inhibition of human plasma butyrylcholinesterase (BChE) may cause side effects. Some of the drugs currently used in the treatment of AD are capable of increasing the cholinergic transmission through the AChE inhibition. In this work we proposed molecular hybrids of tacrine with donepezil (fusion of these structures), in order to suggest new proposals of AChE inhibitors for future treatment of AD. We have analyzed all the structures by docking, density functional studies and drug like properties.     

Discovery of potent inhibitor for matrix metalloproteinase-9 by pharmacophore based modeling and dynamics simulation studies

Matrix metalloproteinase-9 (MMP-9) is an attractive target for anticancer therapy. In the present study ligand based pharmacophore modeling was performed to elucidate the structural elements for a diverse class of MMP-9 inhibitors. The pharmacophore model was validated through Güner-Henry (GH) scoring method. The final pharmacophore model consisted of three hydrogen bond acceptors (HBA), and two ring aromatic regions (RA). This model was utilized to screen the natural compound database to seek novel compounds as MMP-9 inhibitors. The identified hits were validated using molecular docking and molecular dynamics simulation studies. Finally, one compound named Hinokiflavone from Juniperus communis had high binding free energy of −26.54 kJ/mol compared with the known inhibitors of MMP-9. Cytotoxicity for hinokiflavone was evaluated by MTT assay. Inhibition of MMP-9 in the presence of hinokiflavone was detected by gelatin zymography and gelatinolytic inhibition assay. Results revealed that the natural compounds derived based on the developed pharmacophore model would be useful for further design and development of MMP-9 inhibitors.