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At least 127 records · Page 7Linked to original sources
PubMed1996

Evolutionary algorithms in computer-aided molecular design.

In recent years, search and optimisation algorithms inspired by evolutionary processes have been applied with marked success to a wide variety of problems in diverse fields of study. In this review, we survey the growing application of these 'evolutionary algorithms' in one such area: computer-aided molecular design. In the course of the review, we seek to summarise the work to date and to indicate where evolutionary algorithms have met with success and where they have not fared so well. In addition to this, we also attempt to discern some future trends in both the basic research concerning these algorithms and their application to the elucidation, design and modelling of chemical and biochemical structures.

Algorithms↗
PubMed1993

Computer-assisted molecular modeling: indispensable tools for molecular pharmacology.

Ball-and-stick mechanical models, typically associated with chemists, have been helpful in understanding structural problems and the relationship between structure and biologic activity. With progress in computer speed, graphics performance, and software innovation, molecules of biological interest can be subjected to rigorous calculations. Computational chemistry and biology are rooted in the belief that theoretical physics can be used to calculate accurate molecular structures. Although in its infancy, computer-assisted molecular modeling is gaining attention and acceptability as an increasing number of researchers turn their attention toward rational molecular design. The trend to use theoretical methods can be traced to the greater availability of computer graphics work-stations, decreasing computer costs, faster central processing units, more robust algorithms, and "user-friendly" software codes. Every major pharmaceutical company has invested in these resources to reduce the time it takes to design and develop pharmaceutical agents. Because of the vast financial and manpower investments needed to introduce a single drug, medicinal chemists and pharmacologists are interested in understanding and predicting drug action at the molecular level. Although drug action is still poorly understood, molecular modeling should reduce some of the labor in the development of pharmaceutical agents.

Computer Graphics↗
PubMed2005

A molecular dynamics computer simulation study of room-temperature ionic liquids. I. Equilibrium solvation structure and free energetics.

Solvation in 1-ethyl-3-methylmidazolium chloride and in 1-ethyl-3-methylimidazolium hexafluorophosphate near equilibrium is investigated via molecular dynamics computer simulations with diatomic and benzenelike molecules employed as probe solutes. It is found that electrostriction plays an important role in both solvation structure and free energetics. The angular and radial distributions of cations and anions become more structured and their densities near the solute become enhanced as the solute charge separation grows. Due to the enhancement in structural rigidity induced by electrostriction, the force constant associated with solvent configuration fluctuations relevant to charge shift and transfer processes is also found to increase. The effective polarity and reorganization free energies of these ionic liquids are analyzed and compared with those of highly polar acetonitrile. Their screening behavior of electric charges is also investigated.

Journal Article↗
PubMed2001

Quantum computing in molecular magnets.

Shor and Grover demonstrated that a quantum computer can outperform any classical computer in factoring numbers and in searching a database by exploiting the parallelism of quantum mechanics. Whereas Shor's algorithm requires both superposition and entanglement of a many-particle system, the superposition of single-particle quantum states is sufficient for Grover's algorithm. Recently, the latter has been successfully implemented using Rydberg atoms. Here we propose an implementation of Grover's algorithm that uses molecular magnets, which are solid-state systems with a large spin; their spin eigenstates make them natural candidates for single-particle systems. We show theoretically that molecular magnets can be used to build dense and efficient memory devices based on the Grover algorithm. In particular, one single crystal can serve as a storage unit of a dynamic random access memory device. Fast electron spin resonance pulses can be used to decode and read out stored numbers of up to 105, with access times as short as 10-10 seconds. We show that our proposal should be feasible using the molecular magnets Fe8 and Mn12.

Journal Article↗
PubMed1989

Carbamyl analogues of potent nicotinic agonists: pharmacology and computer-assisted molecular modeling study.

To investigate how the substitution of NH2 for CH3 affects the activity of three, potent, semirigid nicotinic agonists, carbamyl analogues were synthesized. The carbamyl agonists were 1-methyl-4-carbamyl-1,2,3,6-tetrahydropyridine methiodide (1), 1-methyl-4-carbamylpiperidine methiodide (2), and 1-methyl-4-carbamylpiperazine methiodide (3). Their potencies (reciprocals of the equipotent molar ratios) at the frog neuromuscular junction with reference to carbamylcholine were 0.77, 0.052, and 0.15, respectively. The acetyl analogues were more potent by factors of 65, 175, and 17, respectively. Explanations for this variable reduction in activity were sought by using computer-assisted molecular mechanics and calculations of electrostatic potential contours. Bioactive conformations of 1-3 were assigned on the basis of a well-supported pharmacophore and the ground-state conformation of the highly potent (50 times that of carbamylcholine) prototype, isoarecolone methiodide (4). Agonist 3 and its acetyl analogue superimposed closely in their ground-state, bioactive conformations, and the differences in their electrostatic potential contours were the least among the three pairs. Accordingly, their potencies differed the least. Agonists 1 and 2 both showed greater differences (with respect to their acetyl analogues) in their electrostatic potential contours and greater differences in potency. Agonist 2, in addition, could achieve the bioactive conformation only at the expense of 2.8 kcal mol-1, and, correspondingly, its activity relative to its acetyl analogue was lowest of all.

Computer Graphics↗
PubMed1998

Small-angle X-ray scattering and computer-aided molecular modeling studies of 20 kDa fragment of porcine amelogenin: does amelogenin adopt an elongated bundle structure?

Amelogenins, which are major matrix constituents in the developing tooth, play a regulatory role in the process of enamel crystal formation. Porcine amelogenin with 173 amino acid residues is rich in proline, glutamine, leucine, and histidine. We utilized the small-angle X-ray scattering (SAXS) technique to examine the solution structure of porcine amelogenin. Samples used were two porcine amelogenins with apparent molecular weights of 20 kDa (amino acids 1 to 148) and 13 kDa (amino acids 46 to 148) on SDS-PAGE. Prior to SAXS measurements, the protein samples were dissolved in 2% (v/v) acetic acid to give a concentration range up to 10 mg/ml. Comparison between Rg (the overall radius of gyration) and Rc (the cross-sectional radius of gyration) revealed that the 20 kDa amelogenin exists in this solution as asymmetric particles with a length of about 15 nm, presumably corresponding of dimers. Based on these experimental data and computer-aided molecular modeling studies, we propose that the 20 kDa amelogenin adopts an elongated bundle structure which mainly consists of extended structures similar to polyproline II and/or beta-strand, interspersed with beta-turn or loop.

Amelogenin↗
PubMed1994

Hydration of cytidine, 2'-deoxycytidine and their phosphate salts in the aqueous solutions. A molecular dynamics computer simulation study.

To compare the hydration pattern of the cytidine (Cyd) and 2'-deoxycytidine (dCyd) in the aqueous solutions at the level of microscopic interactions. Molecular Dynamics (MD) computer simulations have been undertaken. The results indicate that the hydration of the heterocyclic base moiety in cytidine and 2'-deoxycytidine has a hydrophobic character. None of the three potential Watson-Crick base pair centres hydrogen bonds with the water molecules and the formation of something akin to a clathrate cage structure of water around base moieties of nucleosides in the aqueous solution is suggested. In contrast, the hydration of Cyd and dCyd sugar moieties shows a hydrophilic character and the three-dimensional networks of H-bonds involving all hydrophilic centres are formed differently around the ribose and 2'-deoxyribose. The sugar hydroxyl groups participate in the hydrogen bonding with water both as H-donor and as H-acceptor. Their donor-acceptor abilities have been evaluated and compared. The coordination numbers, the geometrical data of the first hydration shell, and the number of hydrogen bonds have been calculated. The changes in the pattern of hydration with the increased concentration of nucleosides and upon nucleoside protonation are discussed. The analysis of the pairwise interaction energies are also presented.

Computer Simulation↗
PubMed1998

A molecular dynamics computer simulation study of nucleotide analogues. Comparison of the hydration pattern of dithymidine phosphate with those of the dithymidine methylphosphonate diastereomers.

The hydration pattern of thymidyl(3'->5') thymidine 1 and those of Rp and Sp diastereomers of the corresponding methylphosphonate analogue 2, have been studied using Molecular Dynamics (MD) computer simulation. It was found that the methylphosphonate modification leads to significant changes in the coordination of water molecules around the internucleotidic linkage and these, in turn, affect the hydration pattern of other parts of the molecule. The most notable differences between Rp and Sp diastereomers 2a and 2b were found to occur at the deoxyribose moieties of the nucleosid-5'-yl units.

Computer Simulation↗
PubMed1991

FASTRUN: a special purpose, hardwired computer for molecular simulation.

We describe the design, construction, and performance of a special purpose, hardwired accelerator for molecular mechanical calculations called FASTRUN. The processor was designed at Columbia University in 1984, constructed in the Instrumentation Division of Brookhaven National Laboratory, and delivered to Columbia in final form in 1989. It was rendered functional for molecular mechanics in early 1990. Together with its host Star array processor, FASTRUN has a measured performance for molecular dynamics simulations which compares favorably with present day supercomputers. The hardware replication cost of FASTRUN is on the order of $100,000.00.

Computer Simulation↗
PubMed1994

A special-purpose computer for molecular dynamics: GRAPE-2A.

Molecular dynamics simulations have been extensively used in research of proteins. Since these simulations are quite computer intensive, their acceleration is of main interest of the research. In molecular dynamics simulations, almost all computing time is consumed in calculating the forces between particles, e.g., Coulomb and van der Waals forces. We have designed and built GRAPE-2A (GRAvity PipE 2A), a special-purpose computer for use in simulations of classical many-body systems. GRAPE-2A calculates forces exerted on a particle from the other particles. GRAPE-2A can calculate force of an arbitrary functional form of a central force. The host computer, which is connected to GRAPE-2A through the VME bus, performs other calculations such as time integration. The peak speed of GRAPE-2A is 180 Mflops. We can also stimulate systems with periodic boundary conditions by the Ewald method, using GRAPE-2A and another special-purpose computer, WINE (Wave space INtegrator for the Ewald method).

Computer Simulation↗
PubMed1998

Theoretical calculation and prediction of brain-blood partitioning of organic solutes using MolSurf parametrization and PLS statistics.

Sixty-three structurally diverse compounds were investigated to statistically model the brain-blood partitioning of organic solutes using theoretically computed molecular descriptors and multivariate statistics. The program MolSurf was used to compute theoretical molecular descriptors related to physicochemical properties such as lipophilicity, polarity, polarizability, and hydrogen bonding. The multivariate Partial Least Squares Projections to Latent Structures (PLS) method was used to delineate the relationship between the brain-blood partitioning of organic solutes and the theoretically computed molecular descriptors. Good statistical models were derived. Properties associated with polarity and Lewis base strength had the largest impact on the blood-brain partitioning and should be kept to a minimum to promote high partitioning. The absence of atoms capable of hydrogen bonding interactions as well as high lipophilicity and the presence of polarizable surface electrons, i.e., valence electrons, were also found to promote high brain-blood partitioning. The results indicate that theoretically computed molecular MolSurf descriptors in conjunction with multivariate statistics of PLS type can be used to successfully model the brain-blood partitioning of organic solutes and hence differentiate drugs with poor partitioning from those with acceptable partitioning at an early stage of the preclinical drug-discovery process.

Blood-Brain Barrier↗
PubMed1994

Computer-assisted molecular modeling of benzodiazepine and thyromimetic inhibitors of the HepG2 iodothyronine membrane transporter.

T3 cellular uptake is inhibited in the presence of benzodiazepines (BZs). The structure-activity relationship of BZ inhibition correlates strongly with halogen substitution of the nonfused phenyl ring and indicates that this ring is required for activity. A structure-activity series of thyromimetic (TH) inhibitors of the HepG2 iodothyronine transporter further point out the critical importance of the amino group of the alanine side chain, its L-stereo configuration, and the size of the substituents of the inner and outer phenyl rings. A third series of compounds, reported to interact at related sites, were inactive as HepG2 iodothyronine transport inhibitors, and therefore the potent inhibitors were restricted to the BZ and TH compounds. Using both of these BZ and TH structure-activity series along with computer-assisted molecular modeling techniques, we determined which chemical structural components were important at the transporter interaction site. By superimposing structures from active chemicals, excluding residues from poor inhibitors, and incorporating molecular electropotential data, we developed a five-point model of BZ conformational similarity to the endogenous transporter ligand, L-T3: the alkyl substitution at the N1 of the BZ ring seems to simulate the alanine side chain of T3, and the electro-negative halogen and oxygen atoms of substituents at R3/R7/R2'/R4' of BZ form a pyramidal pharmacophore that seems to correspond with the 3-l/5-l/3'-l/4'-OH substituents of T3, respectively. These points, suggesting a tilted cross-bow formation, may be sites for ligand interaction with the iodothyronine transporter.

Benzodiazepines↗
PubMed1998

Identification of functional and unfolding motions of cutinase as obtained from molecular dynamics computer simulations.

The implementation of cutinase from Fusarium solani pisi as a fat-stain removing ingredient in laundry washing is hampered by its unfolding in the presence of anionic surfactants. In this work we present molecular dynamics (MD) computer simulations on cutinase and analysis procedures to distinguish the movements related to its functional behavior (e.g., substrate binding) from those related to the unfolding of the enzyme. Two kinds of MD-simulations were performed: a simulation mimicking the thermal motion at room temperature, and several simulations in which unfolding is induced either by high temperature or by using a modified water-protein interaction potential. Essential dynamics analyses (A. Amadei et al., Proteins 17:412-425, 1993) on the simulations identify distinct regions in the molecular structure of cutinase in which the motions occur for function and initial unfolding. The unfolding in various simulations starts in a similar way, suggesting that mutations in the regions involved might stabilize the enzyme without affecting its functionality.

Carboxylic Ester Hydrolases↗
PubMedDate not supplied

[The use of computers in molecular biology studies].

The paper contains a brief review of the studies involving application of computers, carried out at the Institute of Molecular Biology (investigation of the structure and dynamics of nucleic acids; modelling of the DNA-ligand interactions; analysis of the spectral data of different types: electron paramagnetic resonance, magnetic circular dichroism, absorption and fluorescence spectra; analysis of the thin-layer samples labelled by radioactive elements; chromosome analysis).

Animals↗
PubMed2001

"Bite-and-Switch" approach using computationally designed molecularly imprinted polymers for sensing of creatinine.

A method for the selective detection of creatinine is reported, which is based on the reaction between polymerised hemithioacetal, formed by allyl mercaptan, o-phthalic aldehyde, and primary amine leading to the formation of fluorescent isoindole complex. This method has been demonstrated previously for the detection of creatine using creatine-imprinted molecularly imprinted polymers (MIPs) Since MIPs created using traditional methods were unable to differentiate between creatine and creatinine, a new approach to the rational design of a molecularly imprinted polymer (MIP) selective for creatinine was developed using computer simulation. A virtual library of functional monomers was assigned and screened against the target molecule, creatinine, using molecular modelling software. The monomers giving the highest binding score were further tested using simulated annealing in order to mimic the complexation of the functional monomers with template in the monomer mixture. The result of this simulation gave an optimised MIP composition. The computationally designed polymer demonstrated superior selectivity in comparison to the polymer prepared using traditional approach, a detection limit of 25 microM and good stability. The "Bite-and-Switch" approach combined with molecular imprinting can be used for the design of assays and sensors, selective for amino containing substances.

Biosensing Techniques↗
PubMed2006

Computational prediction of oral drug absorption based on absorption rate constants in humans.

Models for predicting oral drug absorption kinetics were developed by correlating absorption rate constants in humans (K(a)) with computational molecular descriptors. The K(a) values of a set of 22 passively absorbed drugs were derived from human plasma time-concentration profiles using a deconvolution approach. The K(a) values correlated well with experimental values of fraction of dose absorbed in humans (FA), better than the values of human jejunal permeability (P(eff)) which have previously been used to assess the in vivo absorption kinetics of drugs. The relationships between the K(a) values of the 22 structurally diverse drugs and computational molecular descriptors were established with PLS analysis. The analysis showed that the most important parameters describing log K(a) were polar surface area (PSA), number of hydrogen bond donors (HBD), and log D at a physiologically relevant pH. Combining log D at pH 6.0 with PSA or HBD resulted in models with Q(2) and R(2) values ranging from 0.74 to 0.76. An external data set of 169 compounds demonstrated that the models were able to predict K(a) values that correlated well with experimental FA values. Thus, it was shown that, using a combination of only two computational molecular descriptors, it is possible to predict with good accuracy the K(a) value for a new drug candidate.

Administration, Oral↗