Drug Design and Molecular Modelling

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Molecular Modelling of the Complex
Polysaccharide Heparan Sulphate

Molecular Modelling of the Complex Polysaccharide Heparan Sulphate

FGF2, like FGF1, has the same common β - trefoil structure and shares approximately 55% homology (Olsen et al., 2003). It is the most studied member of the FGF family because it is involved in a wide range of biological processes including embryonic development; especially in the lungs and limbs of embryos. Here it is the primary inducer of mesoderm formation in embryogenesis (Zhang et al., 2001), is involved in cell growth and tissue repair. FGF2 is a potent angiogenic stimulator which puts it in the forefront for targeted drug design. Angiogenesis is the well known process by which new blood vessels are formed from pre - existing ones. This is a normal process found in wound repair and myocardial infarction; but is also the fundamental step in tumour growth and metastasis. It is an essential process in the transition of a tumour from its dormant to a malignant state (Folkman, 2006). FGF’s are secreted by tumours (known as pro - angiogenic molecules) in an autocrine or a paracrine manner. This is used to determine many cancers by their increasing amount of FGF present (Goodger et al., 2008). Human metastatic melanoma has been found to express high levels of FGF2 (Nikitovic et al., 2008). FGF2 is found in an inactive form in normal tissue but has been found to be activated upon injury, inflammation or in tumour invasion (Casu et al., 2002). Interestingly the inactivation of FGF2 or the target of FGF2 with antibodies can lead to the inhibition of cells (Nikitovic et al., 2008).
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Review on Computational Bioinformatics and Molecular Modelling: Novel Tool for Drug Discovery

Review on Computational Bioinformatics and Molecular Modelling: Novel Tool for Drug Discovery

Form the above study; we can conclude that recent methods of molecular modelling have enriched the field of In-silico Drug Discovery. It provides a collection of important tools for drug design and analysis. Docking is quite fast, robust and takes less time. It provides the scientist with a new approach to target the receptor. This field helps the drug industry to target new proteins and to cure diseases. Its role is extended in new techniques such as genomics, computational enzymology and proteomics search engines. Widely accepted and validated test data should be established to facilitate the comparisons needed to explain the new frontiers of research in this field.
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An integrated approach towards the development of novel antifungal agents containing thiadiazole: synthesis and a combined similarity search, homology modelling, molecular dynamics and molecular docking study

An integrated approach towards the development of novel antifungal agents containing thiadiazole: synthesis and a combined similarity search, homology modelling, molecular dynamics and molecular docking study

Molecular docking is a value added tool in computer aided drug design. It helps us to understand inhibi- tion mechanism of a drug or drug candidate against its target. Ligand similarity search is one of the techniques used for target prediction. This method compares struc- tures of the studied compounds to the compounds with known targets in the databases. For the cases where experimental crystal structures are not available, homol- ogy modelling is used to build protein structure based on a template. Optimization or refinement of protein structures are done through molecular dynamics (MD) simulations.
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DESIGN, MOLECULAR DOCKING STUDIES, IN SILICO DRUG LIKELINESS PREDICTION AND SYNTHESIS OF SOME BENZIMIDAZOLE DERIVATIVES AS ANTIHYPERTENSIVE AGENTSAbdulaziz Hammad G. Alanazi, Md. Tauquir Alam and Mohd. Imran*DOWNLOAD/VIEW

DESIGN, MOLECULAR DOCKING STUDIES, IN SILICO DRUG LIKELINESS PREDICTION AND SYNTHESIS OF SOME BENZIMIDAZOLE DERIVATIVES AS ANTIHYPERTENSIVE AGENTSAbdulaziz Hammad G. Alanazi, Md. Tauquir Alam and Mohd. Imran*DOWNLOAD/VIEW

However, many side effects are also associated with these drugs, for example, proteinurea, rashes, bad mouth odor, arrhythmia, allergic reactions, pancreatitis, alopecia, angioedema, and gastrointestinal disorders. Therefore, scientists are working to develop new ACE inhibitors as well as Angiotensine II receptor antagonists that are safer and effective than these existing drugs. Benzimidazole derivatives are reported to possess diverse biological activities [11,12]. Benzimidazole derivatives have also been reviewed as antihypertensive agents including as inhibitors of the Angiotensin Converting Enzyme (ACE) [13- 15]. Therefore, it was aimed to perform molecular modelling studies and to synthesize some benzimidazole derivatives as angiotensin converting enzyme inhibitors.
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A Review on Bioisosterism: A Rational Approach for Drug Design and Molecular Modification

A Review on Bioisosterism: A Rational Approach for Drug Design and Molecular Modification

Several methods for drug designing have been employing from many decades. Development of novel drug molecule with improved with high efficacy, potency and undesirable side effects have been the aim of the scientists. Bioisosterism represents one such approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. This review will show the role of bioisosterism in the molecular modification as well as in rational drug design and optimization process with the aim to improve pharmacodynamic and pharmacokinetic properties of lead compounds.
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SHORT COMMUNICATION: ESTIMATION AND QUANTITATIVE PREDICTION OF PARTITION COEFFICIENT OF SOME BENZOGLYCOLAMIDE ESTERS

SHORT COMMUNICATION: ESTIMATION AND QUANTITATIVE PREDICTION OF PARTITION COEFFICIENT OF SOME BENZOGLYCOLAMIDE ESTERS

A major goal of Quantitative Structure Property Relationship (QSPR) studies is to find a mathematical relationship between the activity and property under investigation e.g. solubility, LogP, pKa, molar refraction, dipole moment etc. which are related to the structure of the molecule. In the present communication an attempt was made to apply the concept of QSPR in determining and correlating one of the physicochemical properties of some drug molecules belonging to Benzoyloxyacetamide esters with that of in-silico methods. The descriptor of partition coefficient i.e. LogP of eight compounds was experimentally determined and the correlation of LogP values was done with the values obtained from software programs. LogP values obtained from Hyperchem 5.0 ® were found to correlate the best with experimental values. KEYWORDS: QSPR, partition coefficient, Benzoyloxyacetamide, Computer-aided drug design, Molecular modeling.
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Design, Development and Modelling Of Traffic Light System

Design, Development and Modelling Of Traffic Light System

This simple demand-actuated traffic light control system consists of an intersection where heavy traffic flows on main road and very light traffic is present on auxiliary[r]

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High performance simulation of drug release model and mass transport model by using hybrid platform

High performance simulation of drug release model and mass transport model by using hybrid platform

The controlled drug delivery in drug eluting stents exerts an important influence in decreasing restenosis in intravascular stenting. These stents are coated with drug to avoid the re- narrowing of the arterial wall. The drug is directly associated with the original bare metal stents. Drug eluting stents have plus point of a flexible time delivery of a curative drug to the neighboring arterial tissue. It treats the required injuries efficiently having negligible systemic drug interaction. This thesis aims to develop a mathematical model for describing the procedure of drug distribution from stent coating and from arterial wall. For this purpose, a mathematical model of two phase is presented to simulate the transportation of drug between coating and arterial tissue. This two-phase model explores the impact of non-dimensional parameters such as solid liquid mass transfer rate , ratio of accessible void volume to solid volume and Peclet number on drug release and mass concentrations from coating and tissue layers. For better understanding a 2D mathematical model of biodurable stent coating is developed, where the intravascular distribution of drug from an implanted drug eluting stent in arterial wall is simulated. The model integrates reversible drug binding and diffusion of drug in the stent coating. The arterial wall and coating drug diffusivities are examined for the impact of arterial drug uptake and drug release in the coating. The diffusion coefficient of drug , the diffusion coefficients of wall , , and strut embedment play an important role to regulate the
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Review of applications for SIMDEUM, a stochastic drinking water demand model with a small temporal and spatial scale

Review of applications for SIMDEUM, a stochastic drinking water demand model with a small temporal and spatial scale

Quirijns et al., 2013b; Agudelo-Vera et al., 2013a; Pieterse- Quirijns and Beverloo, 2013) for which insight into the max- imum daily drinking water demand and the maximum daily hot water demand, together with a requirement for the mini- mum and maximum flow velocities, leads to a certain pipe diameter; the maximum demand for hot water in 10 min, 1 h or 1 day is used to determine the most appropriate hot water device. The design rules following from SIMDEUM were validated (see Sect. 2.2, Fig. 6) and are now in the of- ficial Dutch guidelines for the design of DWIs in apartment buildings and non-domestic buildings (ISSO-kontaktgroep, 2015). A research project was also conducted for the design of hot water devices in residential DWIs (Pieterse-Quirijns et al., 2015). This study showed that hot water devices can be designed much smaller, thus reducing the waste of en- ergy, when realistic water demands are taken into account. The current Dutch building regulation is based on floor space only; SIMDEUM can complement this as it can also take into account the presence and behaviour of the residents.
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Identification of Parasitic Cysteine Protease Inhibitors using Analog Design, Molecular Docking and Molecular Dynamics Studies

Identification of Parasitic Cysteine Protease Inhibitors using Analog Design, Molecular Docking and Molecular Dynamics Studies

De novo designs process cannot give the approval that all designed analogues or compounds are feasible for chemical synthesis. As per reports, de novo designed molecules requires synthetic feasibility study of the compound for implementing experimental validation of its biological activity. It is always important to consider those compounds which can be synthesized with reasonable effort. Also in many areas of the drug discovery process and medicinal chemistry research, synthetic accessibility (SA) is considered as a major endpoint to measure the potentiality of a compound to estimate ease of synthesis of drug-like molecules is needed. Consequently selected analogues were considered for SA analysis. In this
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Designing combinatorial libraries optimized on multiple objectives.

Designing combinatorial libraries optimized on multiple objectives.

has shifted away from large diverse libraries to the design of smaller libraries that incorporate as much knowledge about the target as is available. At one extreme, the three-dimensional (3D) structure of the biological target may be known, in which case, structure-based methods such as docking or de novo design can be used in an attempt to design compounds that will fit into the binding site (5,6). It is still the case, however, that in most drug discovery programmes the 3D structure of the target is unknown. When several actives and inactives are known it may be possible to generate a model of activity in the form of a quantitative-structure activity relationship (QSAR), the model could then be used to design libraries consisting of compounds with high predicted activities (7). Other approaches are based on similarity methods (8) where compounds are selected based on their 2D or 3D similarity to one or more known active compounds. Diverse libraries are appropriate when a library is to be screened against a range of biological targets or when little is known about the target of interest. As a general rule, the amount of diversity required is inversely related to the amount of information that is available about the target.
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Pharmacoinformatic and molecular docking studies reveal potential novel antidepressants against neurodegenerative disorders by targeting HSPB8

Pharmacoinformatic and molecular docking studies reveal potential novel antidepressants against neurodegenerative disorders by targeting HSPB8

properties of molecules within an organism were predicted for selected compounds by utilizing the AdmetSAR online server. Eight mathematical models (blood–brain barrier penetration, aqueous solubility [logS], carcinogens, acute oral toxicity, Caco2 permeability, cytochrome P450 2D6 inhibition, rat acute toxicity, and human intestinal absorption) were utilized to predict the ADMET characteristics of molecular chemical structures. A variety of toxicities were predicted that are often used in drug design (Table 3). These toxicities help in evaluating pollutants, metabolites, and intermediates, along with adjusting the dose range for animal assays.
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Features In Creating Polymer Forms Of Drugs

Features In Creating Polymer Forms Of Drugs

analogues of heparin, a polysaccharide sulfo-derivative. They have shown anticoagulant, interferon-inducing, and anticancer activities [21]. The Hoechst Company produced the "Perhalen", which is the sodium salt of polyethylene sulfonate as an anticoagulant. It was the first synthetic polyelectrolyte applied in clinical practice, but its production has been stopped now because of high toxicity. Heterochain polyanions containing carboxyl groups, such as carboxymethyl cellulose, carboxyl cellulose, carboxymethyl dextran, alginic acid, and their sodium salts are less toxic than polysulfates. Carbocchic polycarboxylates such as polyacrylic acid and polymethacrylic acid, ethylene/maleic anhydride copolymer are relatively toxic and not subjected to biodegradation due to the polymer skeleton carbocetability. It has been established that the main criterion for high biological activity of polyanions is the high density in the polymer skeleton of isotactic or syndiotactic carboxyl groups with molecular masses over a ten thousand. The above polyanions are referred to carbochain polymers and not subjected to biodegradation in the organism. Biodegradable polyanions include carboxymethylcellulose and periodically oxidized modification of the unsubstituted hydroxyl groups at C2 and C3 positions, periodically oxidized amylose, starch, dextran, microcrystalline cellulose and alginic acid. These polymers have a high density of carboxyl groups and contain ―weak acetal bonds‖. They exhibited weak antiviral and anticancer activity, and a low toxicity. Based on these polymers, a composition containing bound calcium ion in carboxyl groups of interest as a hemostatic agent was developed [22]. For a sufficiently long circulation of these polymers in the body, and their excretion by biodegradation
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Modelling And Control Design Of Quadruple Conical Tank Process With Minimum And Non Minimum Phase Behaviour

Modelling And Control Design Of Quadruple Conical Tank Process With Minimum And Non Minimum Phase Behaviour

processes are highly non-linear and dynamic. Design of Multivariable control system is of great demand in the process industries. Systems with more than one actuating control input and more than one sensor output are considered as Output (MIMO) systems. These systems are one in which interactions are not negligible. This paper describes a multivariable process of a laboratory process, the quadruple conical tank system using which the nonlinearities and uncertainties in industrial process can be analyzed. Here is done using the First principle. Here steady state analysis and on of the quadruple tank system in both minimum and non minimum phase is Process Control Modeling, Design, and Simulation by B.Wayne Bequette, Modern Control Engineering, Fourth Edition by Katsuhiko Ogata; Anna
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Modelling Illegal Drug Participation

Modelling Illegal Drug Participation

The instruments we use to identify the mis-reporting equation are all survey-related which makes them unlikely to be related to drug participation, providing a strong case for iden- ti…cation. The importance of these factors in the mis-classi…cation literature and their statistical signi…cance in the estimated model lend further support to their inclusion in the mis-reporting equation. Explicitly testing the validity of instruments in non-linear models is a di¢cult task (see, for example, Davidson and MacKinnon 1993) and there may also be concerns that some of the instruments such as present and help are correlated with unobserved characteristics and are therefore potentially endogenous. In light of this we therefore perform a series of robustness checks to test whether our results change signi…- cantly with the inclusion and exclusion of the respective identifying variables. Comparing across the resulting marginal e¤ects, we …nd that the results are generally robust to the various speci…cations for marijuana and speed although we observe some di¤erences for cocaine (presumably a result of the very low recorded participation rate). While we do not present the results from the various model speci…cations here due to space constraints, they are available from the authors on request. Instead, in Table 6 we provide a compar- ison of the various speci…cations on the basis of the joint probability of participation and accurate reporting which we contrast with the sample rate of drug participation. Consis- tent with the results relating to the marginal e¤ects, for marijuana and speed the joint probability of participation and accurate reporting mimics the sample rate of participa- tion quite well while we see some di¤erences for cocaine. Thus, in short, our …ndings do not appear to be heavily reliant on the particular choice of identifying variable(s).
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Studies of the Interaction of Au(I)-Phosphole Complexes with DNA and their Relation to Biological Activity

Studies of the Interaction of Au(I)-Phosphole Complexes with DNA and their Relation to Biological Activity

Distribution coefficient (D)-An important physicochemical property that affects the biodistribution of a drug candidate is its lipophilicity. On the molecular level, it provides information about the inter- and intramolecular forces affecting drug transport through lipid structures. Thus, high lipophilicity facilitates the transport of drug through cell membranes [51]. More positive log P values correspond to more lipophilic complexes, whereas more negative log P values correspond to more hydrophilic ones. In addition, the cytotoxic activities of metal complexes against cisplatin-resistant human cancer cells strongly depend on their lipophilicity [52]. We found that all the compounds were lipophilic, namely L 3 (1.32) > C 3 (1.30)
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Synthesis, Antimicrobial, Antioxidant and Molecular Docking Study of Some Novel Bis-1, 2, 4-Triazolo [3, 4-b]-1, 3, 4-Thiadiazoles

Synthesis, Antimicrobial, Antioxidant and Molecular Docking Study of Some Novel Bis-1, 2, 4-Triazolo [3, 4-b]-1, 3, 4-Thiadiazoles

Previous studies suggested that the presence of pyrazole and triazolothiadiazole pharmacophore plays an important role in the enhancement of pharmacological activity. Encouraged by these findings and aiming at synthesizing new hybrid molecules having enhanced biological properties [13,14], we herein report the synthesis of novel series of bis-1,2,4- triazolo[3,4-b]-1,3,4-thiadiazoles starting from aryl sydnones and their antibacterial, antifungal and antioxidant activity. Molecular docking study was also performed.

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Biotransformations in Drug Synthesis: A Green and Powerful Tool for Medicinal Chemistry

Biotransformations in Drug Synthesis: A Green and Powerful Tool for Medicinal Chemistry

Probably, the most representative example is the sitagliptin process used in the commercial manufacture of antidiabetic Januvia®, from Merck, the first marketed oral antihyperglycemic drug belonging to the gliptin family [59]. Sitagliptin can be used either alone or combined with metformin or thiazolidinedione, another oral antihyperglycemic agents in the treatment of Type 2 diabetes mellitus. Sitagliptin is the most widely sold dipeptidyl peptidase-4 (DPP-4) inhibitor in the US and worldwide, reaching sales of 6,358 million USD in 2014 with an expected rise to 7,525 in 2020. Sitagliptin was the second leading antidiabetic product in 2014, after insulin glargine, and is predicted to be the leading product by 2020 [60,61].
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Reactive Oxygen Species and their Interaction with Platelets

Reactive Oxygen Species and their Interaction with Platelets

During trauma, the formation of ROS/RNS leads to direct endothelial damage and elevates the concentration of potent platelet activators such as thrombin. Under increased oxidative stre[r]

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A Review on Anti-Cholesterol Drugs and their Mechanisms

A Review on Anti-Cholesterol Drugs and their Mechanisms

Quantitative Structure-Activity Relationship is performed to determine the pharmacophore requirement that pull out the activity. Also it suggests the favourable and unfavourable interactions around the molecule. 3D-QSAR studies are carried out for drug-ligand binding studies. The application of force field renders significance to the activity of the molecule. Lennard-Jones potential is used for superimposing drug crystallography data with trained set of data of known function. Comparative molecular field analysis (CoMFA) determines the steric and electrostatic fields which are correlated by partial least square regression. 3D QSAR studies on CETP inhibitors proposed hydrophobic fields are the major contributors followed by electrostatic, hydrogen bond donor and steric fields [43]. Studies on QSAR modelling for HMG-CoA reductase inhibitors were carried out in order to narrow down the structural relationship to activity in the diversity of molecules available. With the knowledge of chiral topological indices QSAR modelling predicted HMG-CoA reductase inhibition activity of new chiral isomers. It was evaluated that pyrimidine and pyrrole substitution resulted in partial inhibition of HMG- CoA reductase [44]. Table 1 represents the drug structure and their mechanism. The structure and activity relation is important when it comes to fabricating a potential drug.
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