Alka Kurup

QSAR of Cytochrome P450

The cytochrome P450 class of enzymes is an extremely important and complex group. It has a significant place in ADME (adsorption, distribution, metabolism, elimination) that those developing new drugs must be concerned with. While there are various ways in which organic compounds can undergo metabolic attack, P450 is probably the most important. Recently, Lewis (2000) reviewed his extensive studies on P450 and efforts to use QSAR to gain a deeper understanding on this important class of enzymes. We have also been interested in the QSAR of P450 enzymes, but much has appeared since our last review (Hansch and Zhang, 1993).

HIV-1 Protease Inhibitors: A Comparative QSAR Analysis

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.

Comparative QSAR: On the Toxicology of the Phenolic OH Moiety

In this report we consider the effect of substituents on phenol toxicity and show how the parameters used in Quantitative Structure-Activity Relationships (QSAR) can be used to draw mechanistic inferences of value in understanding the reasons behind the various types of toxicity. In particular, we are interested in gaining clearer insight into mechanisms via the Hammett-type parameters σ, σ−, σ+ and octanol/water partition coefficients. Particular attention is given to the role of radical reactions and their role in attacking DNA to cause cancer or estrogenic toxicity.

QSAR of Chemical Polarizability and Nerve Toxicity. 2

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.

Quantitative structure-activity relationships of phenolic compounds causing apoptosis.

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.

Searching for allosteric effects via QSARs

A study of our database of 7,000 QSARs involving chemical-biological interaction uncovered 11 examples where the QSARs all contain inverted parabolas based on molecular refractivity. That is, biological activity first decreases with increase in MR and then increases. Two of the examples are for enzymes: cyclooxygenase and trypsin. The others are for various receptors. The results seem to be best rationalized by the larger compounds inducing a change in a receptor unit that allows for a new mode of interaction.

Allosteric interactions and QSAR: On the role of ligand hydrophobicity

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.

Searching for allosteric effects via QSAR. Part II

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.

Possible allosteric effects in anticancer compounds

We have found in this report, and an earlier one, that in a variety of instances an inverted parabolic relationship between biological activity and CMR or logP is observed. That is, activity first decreases as CMR or logP increases and then turns about and increases. This could be attributed to the ligands causing a change in the receptor structure. The present report considers QSAR for a variety of resistant and sensitive cancer cells.

QSAR of anticancer compounds. bis(11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides), bis(phenazine-1-carboxamides), and bis(naphthalimides)

QSAR have been developed for the anticancer activity (growth inhibition) of various tumor cells by bis(11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides), bis(phenazine-1-carboxamides), and bis(naphthalimides). Of the seven QSAR, positive hydrophobic interactions are found in only two examples: bis(naphthalimides) versus human colon cancer cells. This is consistent with other QSAR of anticancer compounds where hydrophobic interactions are found to be unimportant.