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1.
Summary. Recently Simmons et al. reported a new mechanism for SARS virus entry into target cells, where MDL28170 was identified as
an efficient inhibitor of CTSL-meditated substrate cleavage with IC50 of 2.5 nmol/l. Based on the molecule fingerprint searching method, 11 natural molecules were found in the Traditional Chinese
Medicines Database (TCMD). Molecular simulation indicates that the MOL376 (a compound derived from a Chinese medicine herb
with the therapeutic efficacy on the human body such as relieving cough, removing the phlegm, and relieving asthma) has not
only the highest binding energy with the receptor but also the good match in geometric conformation. It was observed through
docking studies that the van der Waals interactions made substantial contributions to the affinity, and that the receptor
active pocket was too large for MDL21870 but more suitable for MOL736. Accordingly, MOL736 might possibly become a promising
lead compound for CTSL inhibition for SARS therapy. 相似文献
2.
虚拟筛选是在计算机上对化合物分子进行模拟预筛选,找出容易和药物靶标结合的小分子(配体),从而降低实际实验测试次数,提高药物先导化合物的发现效率。常用的分子对接软件可以用于基于结构的虚拟筛选,寻找配体与靶标的最佳的作用模式和结合构象,并通过打分函数来筛选出潜在的配体。现有的对接软件如AutoDock Vina等在分子对接过程中需要耗费大量时间和计算资源,特别是面对大规模分子对接时,过长的筛选时间不能满足应用需求,因此,本文在最高效的QVina2对接软件基础上,提出一种基于GPU的QVina 2并行化方法QVina2-GPU,利用GPU硬件高度并行体系加速分子对接。具体包括增加初始化分子构象数量,以扩展蒙特卡罗的迭代局部搜索中线程的并行规模,增加蒙特卡罗的迭代搜索的广度以减少每次蒙特卡罗迭代搜索深度,并利用Wolfe-Powell准则改进局部搜索算法,提高了对接精度,进一步减少蒙特卡罗迭代搜索深度,最后,在NVIDIA Geforce RTX 3090平台上在公开的配体数据库上验证了QVina2-GPU的性能,实验表明在保证分子对接精度的基础上,我们提出的QVina2-GPU对Qvina2的平均加速比达到5.18倍,最大加速比达到12.28倍。 相似文献
3.
为确定治疗新型冠状病毒(SARS-CoV-2)感染的候选药物,开展了针对SARS-CoV-2的药物虚拟筛选研究。以SARS-CoV-2的刺突蛋白(S蛋白)和3CL蛋白酶(主蛋白酶)作为药物靶点,以美国食品药品监督管理局(FDA)批准上市的2 726个小分子药物作为候选,通过分子对接方法,筛选出了3种(阿巴瑞克(Abarelix)、西曲瑞克(Cetrorelix)、鞣酸(Tannic acid))与S蛋白具有较强结合能力的小分子药物,1种(戈舍瑞林(Goserelin))与3CL蛋白酶具有较好结合能力的小分子药物,它们理论上都具有抑制新型冠状病毒复制的效果。将靶向3CL蛋白酶的候选药物与辉瑞公司开发的药物Paxlovid进行比较,发现其作用位点均集中于3CL蛋白酶的第130-200位的残基周围,具有相似的结合位点与相互作用。此外也对候选药物的物理与化学性质及与基因相互作用进行了分析。本研究可为开发新型冠状病毒感染的治疗药物提供参考。 相似文献
4.
Solvation plays an important role in ligand‐protein association and has a strong impact on comparisons of binding energies for dissimilar molecules. When databases of such molecules are screened for complementarity to receptors of known structure, as often occurs in structure‐based inhibitor discovery, failure to consider ligand solvation often leads to putative ligands that are too highly charged or too large. To correct for the different charge states and sizes of the ligands, we calculated electrostatic and non‐polar solvation free energies for molecules in a widely used molecular database, the Available Chemicals Directory (ACD). A modified Born equation treatment was used to calculate the electrostatic component of ligand solvation. The non‐polar component of ligand solvation was calculated based on the surface area of the ligand and parameters derived from the hydration energies of apolar ligands. These solvation energies were subtracted from the ligand‐receptor interaction energies. We tested the usefulness of these corrections by screening the ACD for molecules that complemented three proteins of known structure, using a molecular docking program. Correcting for ligand solvation improved the rankings of known ligands and discriminated against molecules with inappropriate charge states and sizes. Proteins 1999;34:4–16. © 1999 Wiley‐Liss, Inc. 相似文献
5.
Jesudass Joseph Sahayarayan Kulanthaivel Soundar Rajan Mutharasappan Nachiappan Dhamodharan Prabhu Ravi Guru Raj Rao Jeyaraman Jeyakanthan Ahmed Hossam Mahmoud Osama B. Mohammed Abubaker M.A. Morgan 《Saudi Journal of Biological Sciences》2020,27(12):3327-3333
Malaria caused by genus Plasmodium, is a parasite which is the main health issue for humans and about half of the population were suffered. An every year, approximately 1.2–2.7 million people died due to malaria globally. Therefore to prevent the spreading of malaria from the glob novel active drugs with specific activities are necessary. The present study aimed to identify novel drug molecule together with the bioinformatic tools for the development of active malarial drugs. As the search for latest anti malarial compound was developed, this work determined six active blends from various drug databases which possess drug-like characteristics and presents a significant anti malarial actions in in-silico level. Compound ID 300238, 889, 76569, 87324, 45678, and Z185397112are a few of the ligands were got from the Toss lab, Maybridge, Cambridge, Life chem, Bitter, and Examine drug databases and docked against hexokinase 1 protein (PDB: 1CZA) with high throughput practical screening (HTVS) using Glide v6.6. Amid the 6 compounds, compound no: 300238 from Toss lab has the greatest docking score of −9.889 kcal/mol targeting 1CZA protein. The active sites of Hexokinase I of protein were determine by using superimposition of the destination and template structure showed similar structural folds and active sites which were decidedly conserved. The quality of hexokinase I protein was considered to be sterically stable where the protein was prepared by utilizing the software protein preparation execute in the Schrodinger suite. Prepared proteins were evaluated using SAVES and the studies of molecular dynamics of the hexokinase, and the GROMACS were performed for protein–ligand complex. The low HOMO-LUMO energy gaps of the compound verified the greater stability of the molecule. Here, the tested drug candidates have good absorption, distribution, metabolism, and excretion (ADME) properties which were established by using QikProp, version 3.4 of Schrodinger. 相似文献
6.
Aldose reductase is an important enzyme in the polyol pathway, where glucose is converted to fructose, and sorbitol is released. Aldose reductase activity increases in diabetes as the glucose levels increase, resulting in increased sorbitol production. Sorbitol, being less cell permeable tends to accumulate in tissues such as eye lenses, peripheral nerves and glomerulus that are not insulin sensitive. This excessive build-up of sorbitol is responsible for diabetes associated complications such as retinopathy and neuropathy. In continuation of our interest to design and discover potent inhibitors of aldo-keto reductases (AKRs; aldehyde reductase ALR1 or AKR1A, and aldose reductase ALR2 or AKR1B), herein we designed and investigated a series of new benzoxazinone-thiosemicarbazones (3a-r) as ALR2 and ALR1 inhibitors. Most compounds exhibited excellent inhibitory activities with IC50 values in lower micro-molar range. Compounds 3b and 3l were found to be most active ALR2 inhibitors with IC50 values of 0.52 ± 0.04 and 0.19 ± 0.03 μM, respectively, both compounds were more effective inhibitors as compared to the standard ALR2 inhibitor (sorbinil, with IC50 value of 3.14 ± 0.02 μM). 相似文献
7.
Summary. Ten years after the establishment of the term proteome, the science surrounding it has yet to fulfill its potential. While
a host of technologies have generated lists of protein names, there are only a few reported studies that have examined the
individual proteins at the covalent chemical level defined as protein species in 1997 and their function. In the current study,
we demonstrate that this is possible with two-dimensional gel electrophoresis (2-DE) and mass spectrometry by presenting clear
evidence of in vivo N-terminal alpha A crystallin truncation and relating this newly detected protein species to alpha crystallin
activity regulation by protease cleavage in the healthy young murine lens. We assess the present state of technology and suggest
a shift in resources and paradigm for the routine attainment of the protein species level in proteomics. 相似文献
8.
Summary. Adrenomedullin (AM) is a potent, long-lasting vasoactive peptide originally isolated from human pheochromocytoma. Since its
discovery, serum and tissue AM expression have been shown to be increased in experimental models and in patients with cardiac
hypertrophy, myocardial infarction and end-stage heart failure with several beneficial effects. Considerable evidence exists
for a wide range of autocrine, paracrine and endocrine mechanisms for AM which include vasodilatory, anti-apoptotic, angiogenic,
anti-fibrotic, natriuretic, diuretic and positive inotropic. Thus, through regulation of body fluid or direct cardiac mechanisms,
AM has additive and beneficial effects in the context of heart disease. Notable molecular mechanisms of AM include cyclic
adenosine monophosphate, guanosine-3′,5′-monophosphate, PI3K/Akt and MAPK-ERK-mediated cascades. Given the endogenous and
multifunctional nature of AM, we consider this molecule to have great potential in the treatment of cardiovascular diseases.
In agreement, early experimental and preliminary clinical studies suggest that AM is a new and promising therapy for cardiovascular
diseases. 相似文献
9.
Drug treatment of patients with schistosomiasis may select for drug-resistant parasites. In this article, we formulate a deterministic model with multiple strains of schistosomes (helminth parasites with a two-host life cycles) in order to explore the role of drug treatment in the maintenance of a polymorphism of parasite strains that differ in their resistance levels. The basic reproductive numbers for all strains are computed, and are shown to determine the stabilities of equilibria of the model and consequently the distribution of parasite phenotypes with different levels of drug tolerance. Analysis of our model shows that the likelihood that resistant strains will increase in frequency depends on the interplay between their relative fitness, the cost of resistance, and the degree of selection pressure exerted by the drug treatments. 相似文献
10.
Summary. The central nervous system (CNS) and the immune system were for many years considered as two autonomous systems. Now, the
reciprocal connections between them are generally recognized and very well documented. The links are realized mainly by various
immuno- and neuropeptides. In the review the influence of the following immunopeptides on CNS is presented: tuftsin, thymulin,
thymopoietin and thymopentin, thymosins, and thymic humoral factor. On the other side, the activity in the immune system of
such neuropeptides as substance P, neurotensin, some neurokinins, enkephalins, and endorphins is discussed. 相似文献
11.
Krzyzanski W 《Journal of mathematical biology》2000,41(6):477-492
The direct pharmacological effect E is described by the E
max
model relating E to the drug plasma concentration C
p
. The area under the effect vs. time curve (AUC
E
) is used as the measurement of the total net pharmacological effect. The drug plasma concentrations are solutions of compartmental
systems of ordinary differential equations with the input terminated after a finite time and controlled in a proportional
manner by a single dose-like parameter. The asymptotics of the time derivative of C
p
for large doses are derived and used as conditions which have to be satisfied by functions for which the asymptotics of the
integral defining AUC
E
are derived. The AUC
E
is proportional to the time T
C>EC50
for which the drug concentration stays above the threshold level EC
50. The threshold EC
50 denotes the drug plasma concentration which elicits 50% of the maximum effect. The parameter T
C>EC50
is proportional to the logarithm of drug dose for large doses and its asymptotics is calculated up to the order o(1) as dose
increases to infinity. The results are applied to basic pharmacokinetic systems.
Received: 7 December 1999 / Revised version: 23 May 2000 / Published online: 23 October 2000 相似文献
12.
Influenza is a yearly seasonal threat and major cause of mortality, particularly in children and the elderly. Although neuraminidase inhibitors and M2 protein blockers are used for medication, drug resistance has gradually emerged. Thus, the development of effective anti-influenza drugs targeting different constituent proteins of the virus is urgently desired. In this light, we carried out molecular docking to predict the binding modes of anti-influenza diketo acid inhibitors in the active site of the PAN subunit of the metalloenzyme RNA polymerase of influenza virus. The calculations suggested that the dianionic forms of the diketo acids should chelate the dinuclear manganese center as dinucleating ligands and sequester it. They also indicated that the diketo acid derivatives with larger hydrophobic substituents should block a hydrophobic cavity in the active site more tightly. These assumptions could adequately explain the enzyme inhibition by these compounds. Furthermore, we designed potential inhibitors by lead optimization of a diketo acid inhibitor from the thermodynamic points of view. Molecular docking results showed that the newly designed diketo acid derivatives might inhibit the metalloenzyme RNA polymerase more strongly than the lead inhibitor. 相似文献
13.
Johannsen B 《Amino acids》2005,29(4):307-311
Summary. Radioactive isotopes are uniquely applicable to observe reactions or circuits of reactions at the molecular level without
disturbing the system being studied. The advent of molecular imaging modalities, particularly positron emission tomography
(PET), is a major breakthrough for the visualisation and quantitative assessment of cellular and molecular processes occurring
in living tissues. The recent development of animal PET scanners that offers 2-mm resolution and is tailored to laboratory
rodent models, has made a further great impact on in vivo biochemistry. With these live-imaging modalities at hand, radiotracer-based technologies allow to look directly at biochemical
distribution and interaction processes. Tremendous progress made in radiotracer chemistry, primarily in carbon-11 and fluorine-18
radiochemistry, and in the design of imaging devices strengthens the usefulness of radiotracers in nuclear medicine and drug
research and development and opens exciting opportunities for new applications, e.g., in food science. 相似文献
14.
Farah Shahid Youssef Saeed Alghamdi Mutaib Mashraqi Mohsin Khurshid Usman Ali Ashfaq 《Saudi Journal of Biological Sciences》2022,29(2):1147-1159
Shigella sonnei is one of the major causes of diarrhea and remained a critical microbe responsible for higher morbidity and mortality rates resulting from dysentery every year across the world. Antibiotic therapy of Shigella diseases plays a critical role in decreasing the prevalence as well as the fatality rate of this infection. However, the management of these diseases remains challenging, owing to the overall increase in resistance against many antimicrobials. The situation necessitates the rapid development of effective and feasible S. sonnei treatments. In the present study, the subtractive genomics approach was utilized to find the potential drug targets for S. sonnei strain Ss046. Various tools of bioinformatics were implemented to remove the human-specific homologous and pathogen-specific paralogous sequences from the bacterial proteome. Then, metabolic pathway and subcellular location analysis were performed of essential bacterial proteins to describe their role in various cellular processes. Only one essential protein i-e Chromosomal replication initiator protein DnaA was found in the proteome of the pathogen that could be used as a potent target for designing new drugs. 3D structure prediction of DnaA protein was carried out using Phyre 2. Molecular docking of 5000 phytochemicals was performed against DnaA to identify four top-ranked phytochemicals (Riccionidin A, Dothistromin, Fustin, and Morin) based on scoring functions and interaction with the active site. This study suggests that these phytochemicals could be used as antibacterial drugs to treat S. sonnei infections in the future. To confirm their efficacy and evaluate their drug potency, further in vitro analyses are required. 相似文献
15.
Summary. Over the years biomedical research has been constantly oriented towards the development of new therapeutics based on bioactive
peptides and their analogues. In particular, the generation of compounds having structures and functions similar to bioactive
peptides, named “peptidomimetics”, raised much interest among organic and medicinal chemists due to the possibility by using
such compounds to improve both potency and stability of peptidic lead compounds. In the context of this research area, unnatural
amino acids are of great interest in drug discovery, and their use as new building blocks for the development of peptidomimetics
with high diversity level and possessing high-ordered structures is of special interest. In particular, medicinal chemistry
has taken advantage of the use of amino acid homologues and of cyclic and polycyclic templates to introduce elements of diversity
for the generation of new molecules as drug candidates. Bicyclic amino acids have been developed as reverse turn mimetics
and dipeptide isosteres, and the constraint imposed by their structures has been reported as a tool for controlling the conformational
preferences of modified peptides. Moreover, synthetic efforts have been driven to the generation of diverse structures based
on the modulation of ring size and scaffold decoration by suitable functional groups. Herein is reported an overview of different
classes of bicyclic amino acids, taking into account the strategies to achieve structurally diverse templates, and some implications
in medicinal chemistry are also disclosed.
Authors’ address: Antonio Guarna, Dipartimento di Chimica Organica “Ugo Schiff” and Laboratorio di Progettazione, Sintesi
e Studio di Eterocicli Bioattivi (HeteroBioLab), Università degli Studi di Firenze, Polo Scientifico e Tecnologico, Via della
Lastruccia 13, I-50019 Sesto Fiorentino, Firenze, Italy 相似文献
16.
Polimeno L Mittelman A Gennero L Ponzetto A Lucchese G Stufano A Kusalik A Kanduc D 《Amino acids》2008,34(3):479-484
Summary. Our labs are focused on identifying amino acid sequences having the ability to react specifically with the functional binding
site of a complementary antibody. Our epitopic definition is based on the analysis of the similarity level of antigenic amino
acid sequences to the host proteome. Here, the similarity profile to the human proteome of an HCV E1 immunodominant epitope,
i.e. the HCV E1315–328HRMAWDMMMNWSPT sequence, led to i) characterizing the immunoreactive HCV E1 315–328 region as a sequence endowed with a low
level of similarity to human proteins; ii) defining 2 contiguous immunodominant linear determinants respectively located at
the NH2 and COOH terminus of the conserved viral antigenic sequence. This study supports the hypothesis that low sequence similarity
to the host’s proteome modulates the pool of epitopic amino acid sequences in a viral antigen, and appears of potential value
in defining immunogenic viral peptide sequences to be used in immunotherapeutic approaches for HCV treatment.
Authors’ address: D. Kanduc, Department of Biochemistry and Molecular Biology, University of Bari, Via Orabona 4, Bari 70125,
Italy 相似文献
17.
Nahid Shahabadi Monireh Falsafi Maryam Maghsudi 《Nucleosides, nucleotides & nucleic acids》2017,36(1):49-65
The interaction of anticancer drug cytarabine with calf thymus DNA (CT-DNA) was investigated in vitro under simulated physiological conditions by multispectroscopic techniques and molecular modeling study. The fluorescence spectroscopy and UV absorption spectroscopy indicated drug interacted with CT-DNA in a groove-binding mode, while the binding constant of UV-vis and the number of binding sites were 4.0 ± 0.2 × 104 L mol?1 and 1.39, respectively. The fluorimetric studies showed that the reaction between the drugs with CT-DNA is exothermic. Circular dichroism spectroscopy was employed to measure the conformational change of DNA in the presence of cytarabine. Furthermore, the drug induces detectable changes in its viscosity for DNA interaction. The molecular modeling results illustrated that cytarabine strongly binds to groove of DNA by relative binding energy of docked structure ?20.61 KJ mol?1. This combination of multiple spectroscopic techniques and molecular modeling methods can be widely used in the investigation on the interaction of small molecular pollutants and drugs with biomacromolecules for clarifying the molecular mechanism of toxicity or side effect in vivo. 相似文献
18.
Ribonucleotide reductase (RNR) is necessary for production of the precursor deoxyribonucleotides for DNA synthesis. Class Ia RNR functions via a stable free radical in one of the two components protein R2. The enzyme mechanism involves long range (proton coupled) electron transfer between protein R1 and the tyrosyl radical in protein R2. Earlier experimental studies showed that p-alkoxyphenols inhibit RNR. Here, molecular docking and molecular dynamics simulations involving protein R2 suggest an inhibition mechanism for p-alkoxyphenols . A low energy binding pocket is identified in protein R2. The preferred configuration provides a structural basis explaining their specific binding to the Escherichia coli and mouse R2 proteins. Trp48 (E. coli numbering), on the electron transfer pathway, is involved in the interactions with the inhibitors. The relative order of the binding energies calculated for the phenol derivatives to protein R2 is correlated with earlier experimental data on inhibition efficiency, in turn related to increasing size of the hydrophobic alkyl substituents. Using the configuration identified by molecular docking as a starting point for molecular dynamics simulations, we find that the p-allyloxyphenol interrupts the catalytic electron transfer pathway of the R2 protein by forming hydrogen bonds with Trp48 and Asp237, thus explaining the inhibitory activity of p-alkoxyphenols. 相似文献
19.
Acetohydroxyacid synthase and its role in the biosynthetic pathway for branched-chain amino acids 总被引:1,自引:0,他引:1
Summary. The branched-chain amino acids are synthesized by plants, fungi and microorganisms, but not by animals. Therefore, the enzymes
of this pathway are potential target sites for the development of antifungal agents, antimicrobials and herbicides. Most research
has focused upon the first enzyme in this biosynthetic pathway, acetohydroxyacid synthase (AHAS) largely because it is the
target site for many commercial herbicides. In this review we provide a brief overview of the important properties of each
enzyme within the pathway and a detailed summary of the most recent AHAS research, against the perspective of work that has
been carried out over the past 50 years. 相似文献
20.
Stomatal opening by fusicoccin is accompanied by depolymerization of actin filaments in guard cells 总被引:6,自引:0,他引:6
Actin in guard cells is assembled in a radial pattern when stomata are induced to open under light, but the filaments are
disassembled when stomata are closed under darkness or by abscisic acid (S.-O. Eun and Y. Lee, 1997, Plant Physiol. 115: 1491–1498).
To test if signals that open stomata commonly generate the polymerized form of actin in guard cells, leaves of Commelina communis L. were treated with a potent stomatal opening agent, fusicoccin, and the actin organization examined by immunolocalization
techniques. When stomata were induced to open by fusicoccin, hardly any of the filamentous form of actin was detected; instead,
the actin resembled that present in guard cells that had been treated with an antagonist to actin filaments, cytochalasin
D, and showed a sharp contrast to the long filaments developed in illuminated guard cells. Furthermore, treatment of illuminated
leaves with fusicoccin disintegrated actin filaments that had already been formed in the guard cells. Preincubation of leaves
with phalloidin, which interferes with fusicoccin-induced actin depolymerization, delayed fusicoccin-induced opening during
the early phase. These observations suggest that the prevention of actin filament formation and/or depolymerization of actin
filaments may accelerate the stomatal opening process in response to fusicoccin.
Received: 1 October 1999 / Accepted: 29 November 1999 相似文献