Biomedical subjects
Publications and source records attributed to Alka Kurup.
Melanoma is one of the most aggressive forms of skin cancer and is currently attracting our attention particularly in the area of quantitative structure-activity relationships (QSAR). In the present review, an attempt has been made to collect the data for different sets of compounds and to discuss their toxicities toward melanoma cells by the formulation of a total number of 36 QSAR.
An allosteric reaction has been found in a variety of instances where an inverted parabolic relationship between biological activity and hydrophobicity is apparent, that is the activity first decreases as hydrophobicity increases and after a certain point, activity begins to increase. This could be attributed to the ligands causing a change in the receptor structure. In this report, the role of hydrophobic properties of chemicals in promoting allosteric reactions have been discussed in term of hydrophobicity (logP) by the formulation of a total number of 50 QSAR equations. The QSAR model of this type may be represented by Eq. I.
Dopamine receptor blockers have been used for the treatment of schizophrenia for many years. We have developed 22 quantitative structure activity relationships (QSAR) for different sets of compounds to understand chemical-biological interactions governing their activities toward dopamine receptors.
Chemical-biological interactions in human are currently attracting our attention particularly in the area of QSAR (quantitative structure-activity relationships). In the present review, an attempt has been made to collect the data for the effect of chemicals in human and discussed by the formulation of a total number of 37 QSAR.
The polarizability of a molecule, an important physical property, is currently attracting our attention particularly in the area of QSAR for chemical-biological interactions. In this report, the polarizability effects on ligand-substrate interactions has been discussed in terms of NVE (number of valence electrons) using additive values for valence electrons and the formulation of a total number of 51 QSAR. The QSAR model can be illustrated by Eq. I. log 1/C = a(NVE) +/- constant
The prediction from structure of ADME (absorption, distribution, metabolism, elimination) of drug candidates is an important goal to achieve since it can considerably reduce the cost of drug development. Using our database of 10,700 QSAR, we are now reaching the point where we can make many useful comparisons that illustrate how ADME is a practical way to describe the way organic compounds react with living systems. We also show that Caco-2 cells are useful to model absorption, but the most generally useful parameter is the octanol/water partition coefficient. It should be noted, however, that in our opinion, an in silico prediction of ADME is still a long way in the future.
A study of a very large database of QSAR (9100) has uncovered a few unusual examples where as one increases the hydrophobicity of the members of a set of congeners, activity decreases until at a certain point, activity begins to increase. Obviously a change in mechanism is involved. The only way we have found to rationalize this unusual event is by a change in the structure of the receptor. We have found this to occur with hemoglobin, a substance first used to define allosteric reactions.
A study of a variety of phenolic compounds (simple phenols, estradiol, bisphenol A, diethylstilbesterol) on their action on L1210 leukemia cells led to the formulation of the following QSAR for apoptosis:log 1/C=-3.16 Clog P+2.77 CMR-3.76n=11, r(2)=0.939, s=0.630, q(2)=0.892C is the molar concentration causing 25% apoptosis, Clog P is the calculated octanol/water partition coefficient and CMR is the calculated molecular refractivity. Our results imply the significance of characterization of the phenolic compounds with apoptotic activity and the development of new agents for cancer therapy.
Allosteric interactions have in the past been established by means of X-ray crystallography or careful study of a single molecule at a variety of concentrations. Here we report a method for using QSAR to establish a change in reaction mechanism by establishing an inversion point. That is, as polarizability of a member of a congeneric set of compounds is increased (as measured by CMR), activity at first decreases until, at the inversion, activity turns around and increases. Out of 23 examples, 14 have inversion points of 10+/-1. This includes a wide variety of receptors such as thrombin, 5-HT, dopamine, and tyrosine kinase acting with a variety of ligands.
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An excellent example in the field of rational drug design is the discovery and development of more than a dozen drugs for the treatment of AIDS. The major targets for the development of new chemotherapeutic agents are Reverse Transcriptase and Protease, the enzymes encoded by HIV-1. The introduction of HIV-1 protease (HIV-1 PR) inhibitors, in particular, has drastically decreased the mortality and morbidity associated with AIDS. The inhibition of this enzyme results in production of immature and noninfectious virions. In the present review, a comparative quantitative structure activity relationship (QSAR) study of various peptidomimetic and non-peptidomimetic molecules investigated for their inhibitory activity has been reported. Among the various physicochemical properties studied, hydrophobicity, steric and electronic interactions are found to play important role in binding to the receptor.
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This report considers the importance of electronic effects in their role in the QSAR of chemical-biological interactions. The problem of accounting for polarizability effects in ligand-substrate interactions is discussed in terms of molecular polarizability (MR) and NVE (number of valence electrons) using additive values for valence electrons. The two approaches give essentially the same result in examples of frog nerve toxicity and examples of nerve toxicity with rabbits and cockroaches. The point is made that no matter how one approaches QSAR, electronic interactions must be considered if we are to begin to develop a science of chemical-biological interactions.
Polarizability is a property of molecules that has long been of interest to scientists from a variety of viewpoints. However, in the area of the QSAR of chemical-biological interactions, it has received little attention. Recently we have shown that one can use the simple summation of the valence electrons (H = 1, C = 4, O = 6, etc.) in a molecule as a measure of its polarizability. We have found this parameter to correlate nerve toxicity of a wide variety of chemicals acting on nerves of frogs, rabbits, cockroaches, and humans.
The C-QSAR program is used to develop and search a database of over 18,000 equations that relate biological or physico-chemical properties of molecules to various molecular descriptors. The data used to derive the quantitative structure activity relationships (QSAR) are taken from various high quality journals. C-QSAR comprises two databases, one for structure-activity information biological systems (n = 9200) and the other for physical organic systems. Users can search the data in 20 different fields; for example by structure or substructure of the compounds involved, by the type of property correlated, by molecular properties, or by properties of the QSAR equation. Various ways in which information can be obtained is briefly discussed. Initially the database is often used for data mining, to search lead molecules, for substituent selection and "model mining" for lateral validation. The regression analysis is useful when the user wants to derive a new QSAR using his structures and activity data.