Biomedical subjects

Simon P Mackay

Publications and source records attributed to Simon P Mackay.

11 recordsLinked to original sources

PubMed2006

Identification of the benzodiazepines as a new class of antileishmanial agent.

The continual increase in drug resistance; the lack of new chemotherapeutic agents; the toxicity of existing agents and the increasing morbidity with HIV co-infection mean the search for new antileishmanial agents has never been more urgent. We have identified the benzodiazepines as a structural class for antileishmanial hit optimisation, and demonstrated that their in vitro activity is comparable with the clinically used drug, sodium stibogluconate, and that the compounds are not toxic to macrophages.

Animals↗

PubMed2006

Symmetrical and unsymmetrical analogues of isoxyl; active agents against Mycobacterium tuberculosis.

Symmetrical and unsymmetrical analogues of the antimycobacterial agent isoxyl have been synthesized and tested against Mycobacterium tuberculosis H37Rv and Mycobacterium bovis BCG, some showing an increased bactericidal effect. In particular, compounds 1-(p-n-butylphenyl)-3-(4-propoxy-phenyl) thiourea (10) and 1-(p-n-butylphenyl)-3-(4-n-butoxy-phenyl) thiourea (11) showed an approximate 10-fold increase in in vitro potency compared to isoxyl, paralleled by increased inhibition of mycolic acid biosynthesis in M. bovis BCG. Interestingly, these isoxyl analogues showed relatively poor inhibition of oleate production, suggesting that the modifications have changed the spectrum of biological activity.

Antibiotics, Antitubercular↗

PubMed2006

The role of water in drug-receptor interactions.

The idea that liquid water is not a uniform and random arrangement of molecules has been taken very seriously by the scientific community. Many experimental and computational investigations show that clathrate- or ice-like structures probably exist at a short time scale in solution. We have designed a new program to simulate water structure around solutes. Our model is based on the geometrical constraints of hydrogen bonding in order to be capable of producing clathrate-like structures. Simulations with small molecules and bio-molecules, using the new software, produce networks of water with specific patterns made of small water rings. The water structures built are consistent with the classification of molecules in terms of structure breaking and making. This approach may give insight into, and a more accurate description of, drug-receptor interactions. The results also suggest that water structure may impart sufficient energy to modify the conformational space of organic molecules through hydrogen bonding.

Computer Simulation↗

PubMed2005

A modelling study of a non-concerted hydrolytic cycloaddition reaction by the catalytic antibody H11.

H11 is the first antibody reported to have dual activity as a non-concerted, Diels-Alderase and hydrolytic catalyst. It was previously shown to catalyse the cycloaddition of acetoxybutadiene 1a to N-alkyl maleimides 2 to afford hydroxy-substituted bicyclic adducts 3 with a 30% ee of a major isomer. To better understand this mechanism and the partial stereospecificity, a homology model of H11 was constructed and used in docking studies to evaluate potential antibody-ligand complexes. The model suggested the hydrolytic nature of H11 was due to Glu 95H acting as a catalytic base, and evaluation of the shape complementarity of the proposed antibody-ligand complexes confirmed at a semi-quantitative level the observation that the major enantiomer is produced in a 30% ee.

Antibodies, Catalytic↗

PubMed2005

Antimalarial benzo[c]phenanthridines.

Analogues of the antimalarial alkaloid nitidine have been prepared with high potency against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. Simple modifications, using an established synthetic route, resulted in an analogue with IC(50) below 5ng/mL against a chloroquine-sensitive strain of P. falciparum. N-Ethylethoxidine had IC(50) below 30ng/mL against both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum.

Animals↗

PubMed2004

Synthesis and antimicrobial activity of some netropsin analogues.

Nine novel lexitropsins were synthesized by linking two netropsin-like moieties through three different dicarboxylic acids; 9,10-dihydro-2,7-phenanthrenedicarboxylic acid; [(3-[[(carboxymethyl)amino]carbonyl]benzoyl)amino]acetic acid and indole-2,5-dicarboxylic acid. The netropsin residues were modified by the use of N-isopentylpyrrole, 5-methylthiophene or 5-isopropylthiazole heterocyclic building blocks in place of the usual N-methylpyrrole. The compounds were tested against five gram-positive bacteria: Staphylococcus aureus, Streptomyces faecalis, methicillin resistant Staphylococcus aureus, Enterobacter cloacae, Mycobacterium fortuitum, three gram-negative bacteria: Klebsiella aerogenes, Proteus vulgaris, Escherichia coli and three fungi: Aspergillus niger, Candida albicans and Aspergillus nidulans. Some of the compounds showed significant inhibitory effects on the growth of the microorganisms.

Anti-Infective Agents↗

PubMed2004

DNA binding of a short lexitropsin.

Footprinting, capillary electrophoresis, molecular modelling and NMR studies have been used to examine the binding of a short polyamide to DNA. This molecule, which contains an isopropyl-substituted thiazole in place of one of the N-methylpyrroles, is selective for the sequence 5'-ACTAGT-3' to which it binds with high affinity. Two molecules bind side-by-side in the minor groove, but their binding is staggered so that the molecule reads six base pairs, unlike the related natural products, which tend to bind to four-base-pair sequences. The result suggests that high affinity and selectivity may be gained without resort to very large molecules, which may be difficult to deliver to the site of action.

Binding Sites↗

PubMed2003

Two very unusual macrocyclic flavonoids from the water lily Nymphaea lotus.

Three novel flavonols, myricetin-3'-O-(6"-p-coumaroyl)glucoside and two epimeric macrocyclic derivatives, as well as the known myricetin-3-O-rhamnoside and pentagalloyl glucose, have been isolated from the wild water lily Nymphaea lotus L. and identified using 2D NMR. This is the first report of such a macrocycle from any source.

Flavonoids↗

PubMed2002

Molecular modelling and cytotoxicity of substituted anthraquinones as inhibitors of human telomerase.

Molecular modelling has been carried out for a number of amine-functionalised anthraquinone derivatives to determine their extent of binding to G-tetraplex DNA and their ability to inhibit the enzymes telomerase and Taq polymerase. The results are compared to data obtained from a modified TRAP assay and show good correlation between the two methods. The findings suggest that anthraquinone derivatives of this type inhibit telomerase by stabilisation of four-stranded tetraplex structures associated with guanine-rich telomeric DNA regions.

Anthraquinones↗

PubMed2002

The lower-generation polypropylenimine dendrimers are effective gene-transfer agents.

OBJECTIVE: To evaluate polypropylenimine dendrimers (generations 1-5: DAB 4, DAB 8, DAB 16, DAB 32, and DAB 64) as gene delivery systems. METHODS: DNA binding was evaluated by measuring the reduced fluorescence of ethidium bromide, and molecular modelling of dendrimer-DNA complexes also was performed. Cell cytotoxicity was evaluated against the A431 cell line using the MTT assay. In vitro transfection was evaluated against the A431 cell line using the beta-galactosidase reporter gene and N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulphate (DOTAP) served as a positive control. RESULTS: Molecular modeling and experimental data revealed that DNA binding increased with dendrimer generation. Cell cytotoxicity was largely generation dependent, and cytotoxicity followed the trend DAB 64 > DAB 32 > DAB 16 > DOTAP > DAB 4 > DAB 8, whereas transfection efficacy followed the trend DAB 8 = DOTAP = DAB 16 > DAB 4 > DAB 32 = DAB 64. CONCLUSION: The generation 2 polypropylenimine dendrimer combines a sufficient level of DNA binding with a low level of cell cytoxicity to give it optimum in vitro gene transfer activity.

DNA↗

PubMedDate not supplied

In silico footprinting of ligands binding to the minor groove of DNA.

The sequence selectivity of small molecules binding to the minor groove of DNA can be predicted by "in silico footprinting". Any potential ligand can be docked in the minor groove and then moved along it using simple simulation techniques. By applying a simple scoring function to the trajectory after energy minimization, the preferred binding site can be identified. We show application to all known noncovalent binding modes, namely 1:1 ligand:DNA binding (including hairpin ligands) and 2:1 side-by-side binding, with various DNA base pair sequences and show excellent agreement with experimental results from X-ray crystallography, NMR, and gel-based footprinting.

Computer Simulation↗