Biomedical subjects

Brian W Clare

Publications and source records attributed to Brian W Clare.

9 recordsLinked to original sources

PubMed2006

A perspective on quantitative structure-activity relationships and carbonic anhydrase inhibitors.

Carbonic anhydrases (CAs, EC 4.2.1.1) are wide-spread enzymes, present in mammals in at least 15 different isoforms. The 12 catalytically active isoforms play important physiological and pathophysiological functions and are strongly inhibited by aromatic/heterocyclic sulfonamides, sulfamides and sulfamates, among others. The catalytic and inhibition mechanisms of these enzymes are understood in great detail, and this greatly helped the design of potent inhibitors, some of which possess important clinical applications as antiglaucoma drugs, or in the management of some neuromuscular disorders. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: many potent CA inhibitors were shown to inhibit the growth of several tumour cell lines in vitro and in vivo, thus constituting interesting leads for developing novel antitumour therapies. The field of quantitative structure-activity relationship (QSAR), formalised by Hansch and others in the early 1960s, is the discovery of empirical relationships between the chemical structure of drugs and their biological activity. The emphasis is on empirical. Extending a QSAR to drugs other than those used to formulate it is always a new hypothesis, and although these extensions are often successful, it should be no cause for surprise if they break down in particular cases. With CA, as with other targets, the descriptor variables that have been used include topological indices, physical properties such as solvent partition coefficients and Hammett constants from reaction rate studies, and quantum theoretical parameters, such as orbital energies, atomic charges, polarisabilities and recently the orientation of nodes in pi-orbitals. This review deals only with the physical and quantum theoretical descriptors.

Animals↗

PubMed2005

A physically interpretable quantum-theoretic QSAR for some carbonic anhydrase inhibitors with diverse aromatic rings, obtained by a new QSAR procedure.

A QSAR based almost entirely on quantum theoretically calculated descriptors has been developed for a large and heterogeneous group of aromatic and heteroaromatic carbonic anhydrase inhibitors, using orbital energies, nodal angles, atomic charges, and some other intuitively appealing descriptors. Most calculations have been done at the B3LYP/6-31G* level of theory. For the first time we have treated five-membered rings by the same means that we have used for benzene rings in the past. Our flip regression technique has been expanded to encompass automatic variable selection. The statistical quality of the results, while not equal to those we have had with benzene derivatives, is very good considering the noncongeneric nature of the compounds. The most significant correlation was with charge on the atoms of the sulfonamide group, followed by the nodal orientation and the solvation energy calculated by COSMO and the charge polarization of the molecule calculated as the mean absolute Mulliken charge over all atoms.

Azo Compounds↗

PubMed2004

Quantum theoretic QSAR of benzene derivatives: some enzyme inhibitors.

Our previously developed approach to the development of QSAR equations for benzene derivatives, originally for phenylalkylamine hallucinogens, has been applied to four new systems: sulfonamide inhibitors of the enzymes carbonic anhydrase, thrombin, trypsin, and Clostridium histolyticum collagenase. The novel features involve the energies and nodal orientations of pi-like orbitals, and an allowance for the symmetry of the benzene nucleus. The resulting equations give better fits, better predictivity and are more easily interpretable than those resulting from traditional QSAR methods.

Benzene Derivatives↗

PubMed2003

Evidence for the S(N)2' mechanism in hydrolysis of C60F48: origin of the stability of trannulenes.

The products of hydrolysis of C60F48 (which contains six isolated double bonds) by either aq. acetone or aq. THF show that no more than twelve fluorines are replaced through nucleophilic substitution, as predicted by the recently identified S(N)2' mechanism. Subsequent HF elimination gives fragments containing a maximum of six epoxide oxygens. Calculated heats of formation of models for the possible initial hydroxy derivatives indicate that there is little energetic discrimination between them, so that a complex mixture is likely to be formed. Overall the data show that hydrolytic degradation of fluorofullerenes is less severe than believed previously, requires a specific motif, and explains the low susceptibility of C60F18 towards hydrolysis and the high stability of trannulenes.

Journal Article↗

PubMed2003

In the first proven SN2' fullerene reaction, both C3 and C1 C60F36 hydrolyse to C1 isomers of C60F35OH that eliminate HF to give epoxides C60F34O; C60F36O oxides are shown to be ethers, and a fourth isomer of C60F36 exists.

On standing in organic solvents containing traces of water, C3 and C1 isomers of C60F36 slowly convert to C1 isomers of C60F35OH. Both fluorofullerenols eliminate HF during EI mass spectrometry to give C60F34O epoxides, one fullerenol being much less stable than the other to the extent that the mass spectrum shows only the epoxide. Both C60F35OH isomers have C1 symmetry, one being identified by the remarkable linear relationship between chemical shifts in its 19F NMR spectrum and those in the spectrum of C1 C60F36; the spectrum of the other shows the pattern of C3 C60F36 rendered asymmetrical by the replacement of one F by OH. The reactions are facilitated by the presence of isolated double bonds, and provide the first proven examples of an SN2' reaction of a fullerene derivative. Our observation explains why only a limited number of fluorines are readily replaced in C60F36 and why C60F18 is by contrast much more resistant to hydrolysis. We have isolated also a pure isomer of C60F36O, which is shown to be an oxahomofullerene (ether) apparently derived from C1 C60F36, and an impure fraction comprising a fourth isomer of C60F36, a trifluoromethyl derivative of C60F36, a second isomer of C60F36O, and an unknown species of 1392 u.

Journal Article↗

PubMed2002

C60F36: there is a third isomer and it has C1 symmetry.

From fluorination of [60]fullerene with MnF3/K2NiF6 at 480 degrees C we have isolated and characterized by both 19F NMR spectrum and single crystal X-ray analysis, a C1 isomer of C60F36; it has three planar delocalized aromatic rings, three short C=C bonds (due to compression from the adjacent fluorines), the longest FC-CF bond (1.684 A) yet found in a fluorofullerene, and its stability is predicted by calculations.

Journal Article↗

PubMed2002

Bacterial protease inhibitors.

Serine-, cysteine-, and metalloproteases are widely spread in many pathogenic bacteria, where they play critical functions related to colonization and evasion of host immune defenses, acquisition of nutrients for growth and proliferation, facilitation of dissemination, or tissue damage during infection. Since all the antibiotics used clinically at the moment share a common mechanism of action, acting as inhibitors of the bacterial cell wall biosynthesis or affecting protein synthesis on ribosomes, resistance to these pharmacological agents represents a serious medical problem, which might be resolved by using new generation of antibiotics, possessing a different mechanism of action. Bacterial protease inhibitors constitute an interesting such possibility, due to the fact that many specific as well as ubiquitous proteases have recently been characterized in some detail in both gram-positive as well as gram-negative pathogens. Few potent, specific inhibitors for such bacterial proteases have been reported at this moment except for some signal peptidase, clostripain, Clostridium histolyticum collagenase, botulinum neurotoxin, and tetanus neurotoxin inhibitors. No inhibitors of the critically important and ubiquitous AAA proteases, degP or sortase have been reported, although such compounds would presumably constitute a new class of highly effective antibiotics. This review presents the state of the art in the design of such enzyme inhibitors with potential therapeutic applications, as well as recent advances in the use of some of these proteases in therapy.

Bacteria↗

PubMedDate not supplied

Predictive flip regression: a technique for QSAR of derivatives of symmetric molecules.

We have for the first time used the flip regression technique to predict the activity of unknown drugs given a substantial series of derivatives of symmetrical molecules such as benzene, with known activity. As descriptors we have used quantum theoretic parameters such as orbital energies and the orientation of pi-orbital nodes and Mulliken charges of atoms. Flip regression is a technique for dealing with multiply substituted derivatives of symmetric molecules, such as phenethylamine or benzenesulfonamide. The method has been tried on two large data sets: thrombin inhibitors and carbonic anhydrase (CA) inhibitors. Multiple validation tests were run, randomly splitting the data into training and test sets and successfully predicting the activity of the test sets, with predictive R2 of around 0.9 for the thrombin inhibitors and 0.7 for the CA inhibitors.

Carbonic Anhydrase Inhibitors↗

PubMedDate not supplied

QSAR of benzene derivatives: comparison of classical descriptors, quantum theoretic parameters and flip regression, exemplified by phenylalkylamine hallucinogens.

A physical model of electronic effects in the QSAR of benzene derivatives, together with a regression technique for finding predictive equations, is presented. The model is simple, based on the quantum theoretic description of the benzene molecule, and accounts for the variance in activity of hallucinogenic phenylalkylamines as well as a classical description in terms of electronic (atomic charge, orbital energy), hydrophobic (Hansch pi) and steric (substituent volume) terms. The new model involves the energies of four pi-like near frontier orbitals and the orientations of their nodes. It is less affected by colinearity than the classical approach. This model more than any other illustrates the essential wave mechanical nature of the interaction of a drug with its receptor, as the pi-like orbitals involved are standing waves of probability of finding an electron in a given location in the field of the atomic nuclei, and have no classical counterpart.

Aniline Compounds↗