Chemistry

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The application of computational tools can alleviate the challenges (viz. time consumption and cost intensiveness) in drug design. Metaheuristics, a collection of such diverse computational and mathematical tools, whose first application was dated back to the early 1970s, caters to several expectations of rational drug designing. Among the population-based metaheuristics, genetic algorithms most closely mimic natural selection. As a consequence, they are rapidly garnering popularity over other members of evolutionary computation as the most preferred simulation processes for drug trials and designing. This chapter discusses various applications of genetic algorithms in drug design, from designing a combinatorial library, QSAR/QSPR study, and designing lead candidacy in drug discovery to solutions for genetic disease. Genetic algorithms find their place in all. © 2014 Springer International Publishing Switzerland. All rights reserved.

(SoNS) School of Natural Sciences

Mathematics

Applications of Metaheuristics in Process Engineering

Genetic algorithms in drug design: A not-so-old story in a newer bottle

A versatile stereoselective diversity oriented synthetic pathway to the possible spiro and fused diverse heterocyclic small molecules is described. The strategy involved the "build-couple-pair" approach involving an S NAr, Michael addition and Mannich reaction on chiral acyl bicyclic lactams 2a/b, followed by a cyclization onto the inbuilt scaffold electrophile, thereby leading to asymmetric fused and spirocyclic nitrogen heterocycles. A "post-pair" phase has been incorporated to generate more polar compounds. We used Principal Component Analysis (PCA) and polar moment of inertia to evaluate the shape-space diversity of our scaffolds with respect to a commercial database and observed extraordinary diversity within the scaffold network. We further calculated the polar surface area (PSA) of our molecules which is an indicator for drug cell permeability. © 2014 The Royal Society of Chemistry.

World University root node

Fulltext

RSC Advances

Pyrrolidine and piperidine based chiral spiro and fused scaffolds via build/couple/pair approach

Effects of acid concentration on excited state intramolecular charge transfer reaction of 4-(azetidinyl) benzonitrile (P4C) in aprotic (acetonitrile and ethyl acetate) and protic (ethanol) solvents have been studied by means of steady state absorption and fluorescence, and time resolved fluorescence spectroscopic techniques. While absorption and fluorescence bands of P4C have been found to be shifted towards higher energy with increasing acid concentration in acetonitrile and ethyl acetate, no significant dependence has been observed in ethanolic solutions. Reaction rate becomes increasingly slower with acid concentration in acetonitrile and ethyl acetate. In contrast, acid in ethanolic solutions does not produce such an effect on reaction rate. Time-dependent density functional theory calculations have been performed to understand the observed spectroscopic results. © Indian Academy of Sciences.

Journal of Chemical Sciences

Effects of acid concentration on intramolecular charge transfer reaction of 4-(azetidinyl) benzonitrile in solution

Peroxidase, such as horseradish peroxidase (HRP), conjugated to antibodies are routinely used for the detection of proteins via an ELISA type assay in which a critical step is the catalytic signal amplification by the enzyme to generate a detectable signal. Synthesis of functional mimics of peroxidase enzyme that display catalytic activity which far exceeds the native enzyme is extremely important for the precise and accurate determination of very low quantities of proteins (fM and lower) that is necessary for early clinical diagnosis. Despite great advancements, analyzing proteins of very low abundance colorimetrically, a method that is most sought after since it requires no equipment for the analysis, still faces great challenges. Most reported HRP mimics that show catalytic activity greater than native enzyme (∼10-fold) are based on metal/metal-oxide nanoparticles such as Fe3O 4. In this paper, we describe a second generation hybrid material developed by us in which approximately 25 000 alkyne tagged biuret modified Fe-tetraamido macrocyclic ligand (Fe-TAML), a very powerful small molecule synthetic HRP mimic, was covalently attached inside a 40 nm mesoporous silica nanoparticle (MSN). Biuret-modified Fe-TAMLs represent one of the best small molecule functional mimics of the enzyme HRP with reaction rates in water close to the native enzyme and operational stability (pH, ionic strength) far exceeding the natural enzyme. The catalytic activity of this hybrid material is around 1000-fold higher than that of natural HRP and 100-fold higher than that of most metal/metal oxide nanoparticle based HRP mimics reported to date. We also show that using antibody conjugates of this hybrid material it is possible to detect and, most importantly, quantify femtomolar quantities of proteins colorimetrically in an ELISA type assay. This represents at least 10-fold higher sensitivity than other colorimetric protein assays that have been reported using metal/metal oxide nanoparticles as HRP mimic. Using a human IgG expressing cell line, we were able to demonstrate that the protein of interest human IgG could be detected from a mixture of interfering proteins in our assay. © 2014 American Chemical Society.

ACS Applied Materials and Interfaces

Fe-TAML encapsulated inside mesoporous silica nanoparticles as peroxidase mimic: Femtomolar protein detection

Water splitting, leading to hydrogen and oxygen in a process that mimics natural photosynthesis, is extremely important for devising a sustainable solar energy conversion system. Development of earth-abundant, transition metal-based catalysts that mimic the oxygen-evolving complex of photosystem II, which is involved in oxidation of water to O2 during natural photosynthesis, represents a major challenge. Further, understanding the exact mechanism, including elucidation of the role of active metal-oxo intermediates during water oxidation (WO), is critical to the development of more efficient catalysts. Herein, we report FeIII complexes of biuret-modified tetra-amidomacrocyclic ligands (Fe-TAML; 1a and 1b) that catalyze fast, homogeneous, photochemical WO to give O2, with moderate efficiency (maximum TON = 220, TOF = 0.76 s-1). Previous studies on photochemical WO using iron complexes resulted in demetalation of the iron complexes with concomitant formation of iron oxide nanoparticles (NPs) that were responsible for WO. Herein, we show for the first time that a high valent FeV(O) intermediate species is photochemically generated as the active intermediate for the oxidation of water to O2. To the best of our knowledge, this represents the first example of a molecular iron complex catalyzing photochemical WO through a FeV(O) intermediate. © 2014 American Chemical Society.

Journal of the American Chemical Society

Homogeneous photochemical water oxidation by biuret-modified Fe-TAML: Evidence of FeV(O) intermediate

An FeV(O) complex has been synthesized from equimolar solutions of (Et4N)2[FeIII(Cl)(biuret-amide)] and mCPBA in CH3CN at room temperature. The FeV(O) complex has been characterized by UV-vis, EPR, Mössbauer, and HRMS and shown to be capable of oxidizing a series of alkanes having C-H bond dissociation energies ranging from 99.3 kcal mol-1 (cyclohexane) to 84.5 kcal mol-1 (cumene). Linearity in the Bell-Evans-Polayni graph and the finding of a large kinetic isotope effect suggest that hydrogen abstraction is engaged the rate-determining step. © 2014 American Chemical Society.

Formation of a room temperature stable Fev(o) complex: Reactivity toward unactivated c-h bonds

The advancement of surface-enhanced Raman scattering (SERS) is significantly increasing as an ultra-sensitive sensing technology in biomedical research. In this review, we focus on the most recent developments of biocompatible nanoprobes for cancer research. First, we discuss coating approaches to enhance the biocompatibility of SERS substrate and Raman reporters. Furthermore, interesting ligands such as antibodies, aptamers and polypeptides are attached to the surface of nanotags for targeting the cancerous cells in vitro. The unique multiplexing capabilities of the SERS technique have been applied for simultaneous multiple target recognition. Finally, these noninvasive, ultrasensitive tools are mostly highlighted for in vivo tumor detection. Potential application of SERS nanotags in therapeutic study and the possibility of SERS nanotags in biomedical applications are outlined briefly in this review. © 2014 Future Medicine Ltd.

Nanomedicine

Biocompatible surface-enhanced Raman scattering nanotags for in vivo cancer detection

Four neutral polynuclear magnetic clusters, [MnIII6MnII2NaI2(N 3)8($\mu$4-O)2(L1) 6(CH3OH)2] (1), [MnIII6NaI2(N3) 4($\mu$4-O)2(L2)4(CH 3COO)4] (2), [NiII5(N 3)4(HL1)4(HCOO)2(CH 3OH)2(H2O)2]{\textperiodcentered}2CH 3OH (3) and [NiII4NaI2(N3)4(HL2)6] {\textperiodcentered}2CH3OH (4) have been synthesized using tetradentate ligands H2L1-2 along with azide as a co-ligand. H 2L1-2 are the products formed in situ upon condensation of 2-hydroxy-3-methoxybenzaldehyde with 1-aminopropan-2-ol and 1-aminopropan-3-ol, respectively. Single crystal X-ray diffraction and bond valence sum calculation showed that complex 1 is composed of both MnIII and MnII. Complex 3 contains coordinated formate, which was formed upon in situ oxidation of methanol. The magnetic study over a wide range of temperatures of all the complexes (1-4) showed that 1 and 2 are antiferromagnetic whereas other two (3-4) are predominantly ferromagnetic. The estimated ground states of the complexes are S ≈ 3(1), S = 4(2), S = 5(3) and S ≈ 4(4), respectively. {\textcopyright} 2013 Elsevier B.V. All rights reserved.

Inorganica Chimica Acta

Tuning nuclearity of clusters by positional change of functional group: Synthesis of polynuclear clusters, crystal structures and magnetic properties

Genetic algorithms (GA) have been widely used in quantitative structure-activity/property relationship (QSAR/QSPR) modeling in recent years and have been shown to generate accurate and robust predictions. In a GA, a population of chromosomes is evolved through the processes of random mutation and crossover and evaluated using a fitness function. Here, we will review the basic principles underlying GA and provide a survey of recent applications in QSAR/QSPR, bioinformatics, and in silico drug design, with particular emphasis on the use of GAs in feature selection and dimensionality reduction, model optimization, conformational search, docking, and diversity analysis. © 2014 Springer International Publishing Switzerland. All rights reserved.

Applications of genetic algorithms in QSAR/QSPR modeling

The application of small molecules to modulate proteins by direct interactions has evolved as a powerful tool for the study of complex biological systems. Conventional genetic approaches have examined biological systems by generating random mutations which were then screened in search of a precise cellular phenotype. Analogous to the genetic approach, large random collections of small molecules can be used to elucidate the roles of specific proteins in many biological pathways. The crux of this 'chemical genetic' approach is the design and synthesis of libraries of compounds which span large tracts of biologically relevant chemical space. Diversity-oriented asymmetric synthesis (DOAS) is an exceptional methodology for preparing structurally and stereochemically diverse small molecule libraries which show a greater variety not only in their physiochemical properties but also in their biological activities. Herein, we describe some of the most effective strategies that have been used in asymmetric diversity-oriented synthesis library design and preparation. 1 Introduction 2 Philosophy of DOAS 3 Stoichiometric Reactions 3.1 DOAS with Chiral Auxiliaries 3.2 DOAS with Chiral Templates 3.3 DOAS with Chiral 'Linchpins' 3.4 DOAS from Natural Products via a Ring-Distortion Strategy 3.5 DOAS via Chiral Reactions 4 DOAS towards Peptidomimetics 5 Catalytic Reactions 6 Conclusion. © Georg Thieme Verlag Stuttgart. New York.