Projects - Methodology

Protein

Description

Statistics

Phosphatidylinositol 3 Kinase (PI3K) regulation of the Akt/PKB pathway is essential for cell survival. Inhibition of PI3K leads to apoptosis (cell death) as a consequence Akt/PKB not phosphorylating proteins including Bad, transcription factors, caspase-9 amd ASK-1. There is reason for thinking that cancer cells would be selectively killed by a PI3K inhibitor.

This query is part of a series which explores the use of less stringent queries that give more hits. We hope to gain an insight into whether better hits are generally included. Test jobs for this query took longer and gave more hits than typical jobs.

Fibroblast growth factor receptor (FGFr) is understood to play a role in blood vessel development in some tumours and was selected as a possible cancer target in the Oxford University-United Devices cancer project. However, our interest is not in FGFr but in the subset of molecules which have been observed to give a high hit rate on this and several very different proteins. The hits from this query will be compared with with those we obtained with some other proteins for the same subset of molecules. This may confirm that it is possible to find molecules which will inhibit multiple targets at the same or explain why these molecules are promiscuous.

Cyclin Dependent Kinase 2 (CDK2) plays an important role in cell cycle regulation and was selected as a possible cancer target in the Oxford University-United Devices cancer project. However, our interest is not in CDK2 but in the subset of molecules which have been observed to give a high hit rate on this and several very different proteins. The hits from this query will be compared with with those we obtained with 821p and 1bzh for the same subset of molecules. This may confirm that it is possible to find molecules which will inhibit multiple targets at the same or explain why these molecules are promiscuous.

The small family of cytochrome P450s play an essential role in the metabolism of certain drug molecules by converting them to more soluble analogues enabling them to be excreted. This query targets the Flavin MonoNucleotide (FMN) binding site of P450 reductase which is likely to associated with electron transfer to at least some P450s.

Protein tyrosine phosphatases and kinases coregulate the critical levels of phosphorylation necessary for intracellular signalling and cell growth. Hence PTP 1B was chosen as a possible cancer target in the Oxford University- United Devices cancer project. However, our interest is not in PTP 1B but in the subset of molecules which have been observed to give a high hit rate on this and several very different proteins. The purpose of the current work is to establish whether it might be possible for the same molecule to bind to PTP 1B and some other protein targets. The hits may also indicate that these molecules have structural features which would explain their promiscuity.

Protein tyrosine phosphatases and kinases coregulate the critical levels of phosphorylation necessary for intracellular signalling and cell growth. Hence PTP 1B was chosen as a possible cancer target in the Oxford University- United Devices cancer project. This current query serves two purposes: to obtain higher quality hits than we did with the Oxford University-United Devices and to compare these hits with those we obtain with 1lyv for the same subset of molecules (1lyv is a protein of the same family).

RAF is activated by RAS binding to it and was selected as a possible cancer target in the Oxford University-United Devices cancer project. However, our interest is not in RAF but in the subset of molecules which have been observed to give a high hit rate on this and several very different proteins. The hits from this query will be compared with with those we obtained with 821p and 1bzh for the same subset of molecules. This may confirm that it is possible to find molecules which will inhibit multiple targets at the same or explain why these molecules are promiscuous.

On 11 July 2003, the number of molecules being processed for this target was increased to allow further comparisons and activity prediction validations.

RAS proteins give a chemical "message" that activate cell growth. Without this signaling factor, the cell doesn't "know" to grow. Inhibiting RAS in cancer cells means an end to their uncontrolled growth.

This query is based on a different crystal structure to 821p and we are interesting in a comparison of the hits. The jobs times do vary but most are completed in less time than typical jobs.

Farnesyltransferase Protein (FTP) activates RAS by binding to it and was selected as a possible cancer target in the Oxford University-United Devices cancer project. However, our interest is not in FTP but in the subset of molecules which have been observed to give a high hit rate on this and several very different proteins. The hits from this query will be compared with with those we obtained with 821p and 1bzh for the same subset of molecules. This may confirm that it is possible to find molecules which will inhibit multiple targets at the same or explain why these molecules are promiscuous.

On 9 July 2003, the number of molecules being processed for this target was increased to allow further comparisons and activity prediction validations.

This is one of several metabolic proteins which may cause undesirable side-effects if a drug interaction occurs. Phenyalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders including phenylketonuria (PKU), non-PKU hyperphenylalaninemia (non-PKU HPA), and variant PKU. A side-effect or drug interaction could cause similar symptoms.

The jobs times are expected to be slightly shorter than typical giving above average numbers of hits.

Serum albumin is an important transport protein in the blood playing a key role in the transport of fatty acids, metabolites, and some drugs. However, one might expect undesirable side-effects from molecules which bind strongly. In addition, such molecules are likely to show exceptional pharmacokinetics with abnormally long retention times in the body.

This query gives very few hits and longer than typical job times.

Phosphatidylinositol 3 Kinase (PI3K) regulation of the Akt/PKB pathway is essential for cell survival. Inhibition of PI3K leads to apoptosis (cell death) as a consequence Akt/PKB not phosphorylating proteins including Bad, transcription factors, caspase-9 amd ASK-1. There is reason for thinking that cancer cells would be selectively killed by a PI3K inhibitor.

This query is being run in order to compare the results and run times from 1.24 with earlier versions.

Phosphatidylinositol 3 Kinase (PI3K) regulation of the Akt/PKB pathway is essential for cell survival. Inhibition of PI3K leads to apoptosis (cell death) as a consequence Akt/PKB not phosphorylating proteins including Bad, transcription factors, caspase-9 amd ASK-1. There is reason for thinking that cancer cells would be selectively killed by a PI3K inhibitor.

This query is being run in order to compare the results and run times from 1.25a with earlier versions.

The small family of cytochrome P450s play an essential role in the metabolism of certain drug molecules by converting them to more soluble analogues enabling them to be excreted. A metabolite made by CYP51 is cholesterol and this protein is therefore of interest in the discovery of anti-cholesterol drugs. Yeast and fungal CYP51 is also inhibited by certain fungicides. At present, we are not considering the differences between animal, plant and fungal CYP51 which would be necessary in order to design selective inhibitors.

We plan to process a series of P450s as their crystal structure become available. Initially we checking for strong inhibitors but with THINK v1.22 we will also be able to predict whether a molecule is likely to be metabolised by P450.

The small family of cytochrome P450s play an essential role in the metabolism of certain drug molecules by converting them to more soluble analogues enabling them to be excreted. A metabolite made by CYP51 is cholesterol and this protein is therefore of interest in the discovery of anti-cholesterol drugs. Yeast and fungal CYP51 is also inhibited by certain fungicides. At present, we are not considering the differences between animal, plant and fungal CYP51 which would be necessary in order to design selective inhibitors.

The query is based on a different crystal structure to 1E9X which had a different bound ligand. The dependence of the results on amino-acid side-chain orientation may be reviewed at a later date.

We plan to process a series of P450s as their crystal structure become available. Initially we checking for strong inhibitors but with THINK v1.22 we will also be able to predict whether a molecule is likely to be metabolised by P450.

In general, a drug which in addition to its intended action interferes with the normal metabolic processing or signalling is likely to exhibit side-effects. It has also been suggested that Aldose Reductase can mediates certain diabetic complications such as hyperglycemia; metabolises toxic aldehydes; and stimulates an inflammation response.

In test jobs, this query gave more hits than usual taking less time than typical jobs.

The small family of cytochrome P450s play an essential role in the metabolism of certain drug molecules by converting them to more soluble analogues enabling them to be excreted. This crystal structure is thought to be similar to human P450 3A4 for which no structure is currently available.

We plan to process a series of P450s as their crystal structure become available. Initially we checking for strong inhibitors but with THINK v1.22 we will also be able to predict whether a molecule is likely to be metabolised by P450.

The small family of cytochrome P450s play an essential role in the metabolism of certain drug molecules by converting them to more soluble analogues enabling them to be excreted. CYP119 is considered similar to some of the other P450s. We are not expected a high hit rate as the binding site is small compared to the size of many drug molecules.

We plan to process a series of P450s as their crystal structure become available. Initially we checking for strong inhibitors but with THINK v1.22 we will also be able to predict whether a molecule is likely to be metabolised by P450.

Fibroblast growth factor receptor-1 (FGFr-1) is understood to play a role in signalling blood vessel development in which there has been renewed interest recently. It is recognised that VEFGr plays a key role in blood vessel development and it is suggested that inhibition of FGFr-1 may be an alternative to inhibiting VEGFr with fewer side-effects.

This query is part of a series which explores the use of less stringent queries that give more hits. We hope to gain an insight into whether better hits are generally included. Test jobs gave more hits and took longer than average jobs.

Serum albumin is an important transport protein in the blood playing a key role in the transport of fatty acids, metabolites, and some drugs. However, one might expect undesirable side-effects from molecules which bind strongly. In addition, such molecules are likely to show exceptional pharmacokinetics with abnormally long retention times in the body. This query is based on an alternative site in a different protein crystal structure to 1e7a-q1.

This query gave above average numbers of hits and job times.

This is a representative of the many kinases which play key roles in facilitating growth of cancer cells. Two queries (1ir3-q3 and 1ir3-q4) have been run over a subset of 3147 jobs to determine the effect of changing the random derivatives generated. For 1ir3-q4, the number of derivatives sought per molecule was increased from 100 to 1000.

This is a representative of the many kinases which play key roles in facilitating growth of cancer cells. Two queries (1ir3-q3 and 1ir3-q4) have been run over a subset of 3147 jobs to determine the effect of changing the random derivatives generated. For 1ir3-q4, the number of derivatives sought per molecule was increased from 100 to 1000.

The small family of cytochrome P450s play an essential role in the metabolism of certain drug molecules by converting them to more soluble analogues enabling them to be excreted. This protein exhibits small conformational changes which appear to an increase in affinity. We anticipate a higher hit rate than many other P450s with most jobs completing in under 5 hours on a "typical (1.2GHz) PC".

We plan to process a series of P450s as their crystal structure become available. Initially we checking for strong inhibitors but with THINK v1.22 we will also be able to predict whether a molecule is likely to be metabolised by P450.

The small family of cytochrome P450s play an essential role in the metabolism of certain drug molecules by converting them to more soluble analogues enabling them to be excreted. This protein exhibits an "open conformation" which appear to increase in the number of molecules which bind. We anticipate a high hit rate with jobs completing in under 20 hours on a "typical (1.2GHz) PC".

We plan to process a series of P450s as their crystal structure become available. Initially we checking for strong inhibitors but with THINK v1.22 we will also be able to predict whether a molecule is likely to be metabolised by P450.

Antibiotic resistance acquired by bacterial organisms often involves the bacteria making an enzyme that converts the antibiotic molecule into an inactive form. One strategy to overcome this inhibits the enzyme that confers resistance with another drug molecule, thereby protecting the antibiotic agent. In the case of the antibiotic virginiamycin the nosocomial pathogen enterococcus faecium has achieved resistance by producing an acetyltransferase.

Antibiotic resistance acquired by bacterial organisms often involves the bacteria making an enzyme that converts the antibiotic molecule into an inactive form. One strategy to overcome this inhibits the enzyme that confers resistance with another drug molecule, thereby protecting the antibiotic agent. In the case of the antibiotic virginiamycin the nosocomial pathogen enterococcus faecium has achieved resistance by producing an acetyltransferase.

This query uses a slightly different scoring function which is expected to give fewer but better hits than 1KHR-Q3.

Two-thirds of solid tumors arise from epithelial tissues, and studies suggest that EGFR inhibitors can stabilize or shrink many of these malignancies. It is conceivable that EGFR inhibitors could beneficial in therapies for cancers of the lung, pancreas, head and neck, breast, prostate, colon, stomach, ovaries, and brain. However, the initial inhibitors in clinicals trials where less successful than expected. In this project, we hope to find more effective molecules.

This query is a variation of 1m17-q2 which we hope will give more and better hits. Job times will be longer than 1m17-q2.

The small family of cytochrome P450s play an essential role in the metabolism of certain drug molecules by converting them to more soluble analogues enabling them to be excreted. In general, drugs that a rapidly metabolised and excreted need to be used in higher doses while molecules than inhibit P450s may cause side-effects or unexpected complications when used with other drug molecules.

This crystal structure was co-crystallised with a small substrate, although the binding site is larger enough to accomodate typical drug molecules, we are not expecting a high hit rate.

The small family of cytochrome P450s play an essential role in the metabolism of certain drug molecules by converting them to more soluble analogues enabling them to be excreted. In general, drugs that a rapidly metabolised and excreted need to be used in higher doses while molecules than inhibit P450s may cause side-effects or unexpected complications when used with other drug molecules.

We plan to process a series of P450s as their crystal structure become available. Initially we checking for strong inhibitors but with THINK v1.22 we will also be able to predict whether a molecule is likely to be metabolised by P450.

The small family of cytochrome P450s play an essential role in the metabolism of certain drug molecules by converting them to more soluble analogues enabling them to be excreted. In general, drugs that a rapidly metabolised and excreted need to be used in higher doses while molecules than inhibit P450s may cause side-effects or unexpected complications when used with other drug molecules.

We plan to process a series of P450s as their crystal structure become available. Initially we checking for strong inhibitors but with THINK v1.22 we will also be able to predict whether a molecule is likely to be metabolised by P450.

Dipeptidyl peptidase IV (DPPIV) belongs to the serine protease family. It removes a dipeptide chain consisting of two amino acids from its peptide substrates. DPPIV has been suggested as a possible target for type II diabetes drugs. However, our interest in this query is to compare the results with 1n1m-q1 which uses the human rather than pig form of the enzyme. This 1orw structure is also lower resolution than 1n1m.

The jobs for this query often take longer than typical jobs giving more hits.

The small family of cytochrome P450s play an essential role in the metabolism of certain drug molecules by converting them to more soluble analogues enabling them to be excreted. This protein exhibits a "closed conformation" in contrast with 1k2o which has an "open conformation".

We plan to process a series of P450s as their crystal structure become available. Initially we checking for strong inhibitors but with THINK v1.22 we will also be able to predict whether a molecule is likely to be metabolised by P450.

It has been suggest that this protein is similar to Protein Kinase C (PKC) which we have considered a cancer target. This and other queries, will help us understand how hits can vary between similar targets. 1szm also has a lower resolution that 1xjd (the PKC cancer query).

The jobs for this query often take longer than typical jobs giving more hits.

Histone deacetylases (HDACs) are essential to removing of acetyl groups from histone proteins which in turn have a pivotal role in gene expression. It has been suggested that HDAC inhibitors may be useful in the treatment of several types of cancers.

Our main interest in this query is to compare the results with those from 1w22-q1 and 1t69-q1 which are different crystal structures. 1w22-q1 job times appear to be shorter than typical jobs giving relatively few hits.

RAS proteins give a chemical "message" that activate cell growth. Without this signaling factor, the cell doesn't "know" to grow. Inhibiting RAS in cancer cells means an end to their uncontrolled growth. This query is part of a series which explores the use of less stringent queries that give more hits. We hope to gain an insight into whether better hits are generally included.

Test jobs gave many more hits and took longer than average jobs.

Protein tyrosine phosphatases and kinases coregulate the critical levels of phosphorylation necessary for intracellular signalling and cell growth. Hence PTP 1B was chosen as a possible cancer target in the Oxford University- United Devices cancer project. However, our interest is not in PTP 1B but in the subset of molecules which have been observed to give a high hit rate on this and several very different proteins. The purpose of the current work is to establish whether it might be possible for the same molecule to bind to PTP 1B and some other protein targets. The hits may also indicate that these molecules have structural features which would explain their promiscuity.

No new jobs are being allocated for this query. Instead the faster 1bzh-q5 is being processed.