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Biomedical subjects

Ajay

Publications and source records attributed to Ajay.

10 recordsLinked to original sources
PubMed2006

Kinase patent space visualization using chemical replacements.

Here we present a methodology for characterizing the structure of patented chemical space. This approach identifies those chemical replacements that can connect sets of exemplified compounds in individual patents. Chemists can then search these replacements to help them discover the architecture within their patent space of interest. To demonstrate the utility of such an approach, we characterize a set of kinase inhibitors from patents and literature and find that many companies' patents can be understood to be straightforward modifications of competitors' patents. By reapplying these same chemical themes to other related compound series, novel, biologically active compounds can be discovered.

Databases, Factual↗
PubMed2006

Integrating data on DNA copy number with gene expression levels and drug sensitivities in the NCI-60 cell line panel.

Chromosome rearrangement, a hallmark of cancer, has profound effects on carcinogenesis and tumor phenotype. We used a panel of 60 human cancer cell lines (the NCI-60) as a model system to identify relationships among DNA copy number, mRNA expression level, and drug sensitivity. For each of 64 cancer-relevant genes, we calculated all 4,096 possible Pearson's correlation coefficients relating DNA copy number (assessed by comparative genomic hybridization using bacterial artificial chromosome microarrays) and mRNA expression level (determined using both cDNA and Affymetrix oligonucleotide microarrays). The analysis identified an association of ERBB2 overexpression with 3p copy number, a finding supported by data from human tumors and a mouse model of ERBB2-induced carcinogenesis. When we examined the correlation between DNA copy number for all 353 unique loci on the bacterial artificial chromosome microarray and drug sensitivity for 118 drugs with putatively known mechanisms of action, we found a striking negative correlation (-0.983; 95% bootstrap confidence interval, -0.999 to -0.899) between activity of the enzyme drug L-asparaginase and DNA copy number of genes near asparagine synthetase in the ovarian cancer cells. Previous analysis of drug sensitivity and mRNA expression had suggested an inverse relationship between mRNA levels of asparagine synthetase and L-asparaginase sensitivity in the NCI-60. The concordance of pharmacogenomic findings at the DNA and mRNA levels strongly suggests further study of L-asparaginase for possible treatment of a low-synthetase subset of clinical ovarian cancers. The DNA copy number database presented here will enable other investigators to explore DNA transcript-drug relationships in their own domains of research focus.

Antineoplastic Agents↗
PubMed2004

Comparative effectiveness of cattle manure, poultry manure, phosphocompost and fertilizer-NPK on three cropping systems in vertisols of semi-arid tropics. II. Dry matter yield, nodulation, chlorophyll content and enzyme activity.

A field experiment was conducted on a deep Vertisol of Bhopal, India to compare root and shoot biomass, chlorophyll content, enzyme activity and nodulation in three cropping systems at three combinations of organic manure and inorganic-fertilizer: 75%NPK + 5 t farmyard manure (FYM), 75%NPK + 1.5 t poultry manure (PM), and 75%NPK + 5 t phosphocompost (PC) vis-a-vis 0%, 75% and 100% of fertilizer-NPK. In general, nodule number and its mass were lower in intercrop soybean than sole soybean. Also there was decrease in the nodule number with higher NPK dose. The FYM treated plots recorded 22.0% and 7.6% higher nodule mass than poultry manure and phosphocompost plots, respectively. Also, the total chlorophyll content was higher in organically treated plots than that in 100% NPK particularly at 30 days after sowing (DAS, pre-flowering). In sorghum the peak nitrate reductase (NR) activity was recorded at 60 DAS while in soybean it was at 30 DAS. The NR activity was higher in intercrop sorghum than that in sole sorghum. Maximum NR activity was observed in 100% NPK. Soybean/sorghum intercropping system recorded significantly higher root and shoot biomass than sole soybean and sorghum. The crop growth rates were relatively rapid during 30-60 DAS and followed the order; intercropping > sole sorghum > sole soybean. With the increase in NPK dose from 0% to 100% there was significant improvement in the dry matter (DM) production in sole sorghum and soybean/sorghum intercropping system. Soybean as preceding crop recorded the highest DM, chlorophyll content, NR activity in wheat while these values were the lowest in sorghum-wheat system.

Agriculture↗
PubMed2002

Predicting drug-likeness: why and how?

There exists a huge attrition rate of molecules in clinical trials. It was expected that high-throughput screening and combinatorial chemistry would make the task of producing drugs easier. However, the efforts of the past decade have not been an unvarnished success. As a result, a lot of experimental and computational efforts are currently being directed at determining the basic requirements for a molecule to become a drug. Here we will review the physiological, structural, and other requirements for obtaining a molecule that will be successful in the clinic. Following this we will provide a description, analysis, and commentary on the computational efforts in this direction. We will focus both on the traditional computational chemistry perspective of starting from the structure of the molecule as well as the traditional computational pharmaceutical scientist's perspective of physiologically based simulations. We end with a few comments about the future and some ideas on re-organizing the pharmaceutical enterprise.

Animals↗
PubMed1999

Designing libraries with CNS activity.

Library design is an important and difficult task. In this paper we describe one possible solution to designing a CNS-active library. CNS-actives and -inactives were selected from the CMC and the MDDR databases based on whether they were described as having some kind of CNS activity in the databases. This classification scheme results in over 15 000 actives and over 50 000 inactives. Each molecule is described by 7 1D descriptors (molecular weight, number of donors, number of acceptors, etc.) and 166 2D descriptors (presence/absence of functional groups such as NH(2)). A neural network trained using Bayesian methods can correctly predict about 75% of the actives and 65% of the inactives using the 7 1D descriptors. The performance improves to a prediction accuracy on the active set of 83% and 79% on the inactives on adding the 2D descriptors. On a database with 275 compounds where the CNS activity is known (from the literature) for each compound, we achieve 92% and 71% accuracy on the actives and inactives, respectively. The models we construct can therefore be used as a "filter" to examine any set of proposed molecules in a chemical library. As an example of the utility of our method, we describe the generation of a small library of potentially CNS-active molecules that would be amenable to combinatorial chemistry. This was done by building and analyzing a large database of a million compounds constructed from frameworks and side chains frequently found in drug molecules.

Animals↗
PubMed1999

The SHAPES strategy: an NMR-based approach for lead generation in drug discovery.

BACKGROUND: Recently, it has been shown that nuclear magnetic resonance (NMR) may be used to identify ligands that bind to low molecular weight protein drug targets. Recognizing the utility of NMR as a very sensitive method for detecting binding, we have focused on developing alternative approaches that are applicable to larger molecular weight drug targets and do not require isotopic labeling. RESULTS: A new method for lead generation (SHAPES) is described that uses NMR to detect binding of a limited but diverse library of small molecules to a potential drug target. The compound scaffolds are derived from shapes most commonly found in known therapeutic agents. NMR detection of low (microM-mM) affinity binding is achieved using either differential line broadening or transferred NOE (nuclear Overhauser effect) NMR techniques. CONCLUSIONS: The SHAPES method for lead generation by NMR is useful for identifying potential lead classes of drugs early in a drug design program, and is easily integrated with other discovery tools such as virtual screening, high-throughput screening and combinatorial chemistry.

IMP Dehydrogenase↗
PubMed1999

Recognizing molecules with drug-like properties.

A variety of successful approaches to the problem of recognizing 'drug-like' molecules have been employed. These range from simple counting schemes such as the Lipinski 'rule of five' to the analysis of the multidimensional 'chemistry space' occupied by drugs, to neural network learning systems. With this variety of tools, it now appears possible to design libraries that are enriched in compounds which have desirable or 'drug-like' properties. Verifying the robustness of these methods, and extending them, will form the basis of research in this field during the next few years.

Administration, Oral↗
PubMed1993

A unified framework for using neural networks to build QSARs.

We propose a new neural network architecture that explicitly separates linear and nonlinear contributions to the biological activity. To facilitate the use of neural networks as a regular tool we demonstrate that (1) a perceptron with linear output units is equivalent to multiple linear regression and (2) one hidden unit at a time can be added to the network so that QSAR data can be modeled by everything from the simplest linear hypersurfaces to complicated ones. The significant improvements accrued by the use of weight decay are demonstrated. We conclude that models built without attempting weight decay may not be reliable either for interpretation or extrapolation. Finally we compare models generated by neural networks, rank regression, and standard regression on non-normally distributed data and conclude that neural networks like rank regression bring out many facets of the data that are inaccessible to multiple linear regression. All the experiments were done on either triazine inhibition of pure DHFR from L1210 leukemia cells and on the inhibition of intact L1210 leukemia cells sensitive and resistant to methotrexate or on steroid binding to progesterone.

Animals↗