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Ethnobotanical
Leaflets 12: 801-10. 2001. Prediction of Biological Activity Spectra for Few
Anticancer Drugs Derived from Plant Sources A. John De Britto*, T. Leon Stephan Raj
and D. Abiya Chelliah PG & Research Department
of Plant Biology and Biotechnology St.Xavier’s
College (Autonomous) Tirunelveli – 627 002, Tamilnadu, India *E-mail:
bjohnde@yahoo.co.in Tel: 0462-2560813; Fax: 0462-2561765 Issued
ABSTRACT Over the past decade plants have become an interesting source of new classes of pharmacologically active natural products. Some secondary metabolites are also well known for their effectiveness on living species. The PASS (Prediction of Activity Spectra for Substances) computer program, which is able to simultaneously predict more than one thousand biological and toxicological activities from only the structural formulas of the chemicals, was used to predict the biological activity profile of 7 secondary metabolites. PASS predictions were successfully compared to the available information on the pharmacological and toxicological activity of these compounds. INTRODUCTION Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. If the spread is not controlled, it can result in death. Cancer is caused by both external factors (tobacco, chemicals, radiation, and infectious organisms) and internal factors (inherited mutations, hormones, immune conditions, and mutations that occur from metabolism). These causal factors may act together or in sequence to initiate or promote carcinogenesis. When the control signals in one of the cell goes wrong, and its life cycle becomes disturbed, it divides and divides. It continues multiplying uncontrollably, and the result of this accumulation of abnormal cells is a mass of cells called a "tumor". A tumor can be either benign or malignant. Benign tumors are non-cancerous and are rarely life-threatening. They do not spread (metastasize) to other parts of the body. Many breast lumps, for example, are benign tumors. Malignant tumors are cancerous and can spread to other parts of the body. When a malignant tumor spreads, the malignant cells break off and travel through the blood lymph system to other places in the body to settle and multiply; or metastasize, resulting in a new tumor called a secondary tumor, or metastasis. The name given to the cancer, however, is reflective of the origin of the cancer, even if it has spread to other areas of the body. For example, if prostate cancer has spread to the liver it is called metastatic prostate cancer. Ten or more years often pass between exposure to external factors and detectable cancer. Cancer is treated with surgery, radiation, chemotherapy, hormone therapy, biological therapy, and targeted therapy. As it is difficult to differentiate between the cancerous and normal cells in-vivo the innovation of a potential drug against the disease it yet a menace. With the known therapeutic knowledge and indigenous crude custom scientists have been thriving their excellence in the field of pharmacology to design a potential drug that is suited to kill the cancerous cells alone. Most
anti-cancer drugs act by inhibiting PASS
predicts simultaneously several hundreds of biological activities (pharmacological
main and side effects, mechanisms of action, mutagenicity,
carcinogenicity, teratogenicity and embryotoxicity). The biological activity spectrum of a
compound presents all compounds’ actions despite the difference in essential
conditions of its experimental determination. If the difference in species,
sex, age, dose, route, etc. is neglected, the biological activity can be
identified only qualitatively. Thus, "the biological activity
spectrum" is defined as the "intrinsic" property of a compound
depending only on its structure and physico-chemical
characteristics. PASS is
the product of ideas originated more than 25 years ago within the framework
of the National Registration System of New Chemical Compounds organized in
the USSR in 1972 (Burov et al., 1990). It was V.Avidon who
suggested that many kinds of biological activity could be predicted on the
basis of structural formulae of chemical compounds (Avidon,
1974). Similar approach was under development by V.Golender
and A.Rozenblit (Golender,
and Rosenblit, 1983). PASS has already found new leads with antiulcer, antitumor and antiamnestic activity, and discovered new mechanism of
action for some compounds with known effect (Filimonov and Poroikov, 1996, Filimonov et al., 1995, Poroikov
and Staraya Kupavna,
1995, Poroikov et
al., 1996, Poroikov et al., 1994). Experimental determination of drug efficacy
and safety is time- and cost-consuming procedure. There exist standard tests
for drug safety assessment (Maggon et. al.,
1992) and different strategies for search of new lead compounds ( Prediction
of this spectrum by PASS is based on SAR analysis of the training set
containing more than 35,000 compounds which have more than 500 kinds of
biological activity (http://www.ibmh.msk.su/PASS). Therefore, PASS once
trained is able to predict simultaneously all biological activities which are
included in the training set. To provide the best quality of prediction new
information about biologically active compounds is collected permanently from
papers and electronic sources and, after the experts' evaluation, is
regularly added to the training set. MATERIALS The
following chemical compounds were selected for the study,
the predicted structures are obtained from the Pub-Chem
database of 1. Taxol 2. Vinblastine 3. Vincristine 4. Topotecan (a camptothecin derivative) 5. Irinotecan 6. Etoposide 7. Teniposide
CHEMICAL
STRUCTURE OF ANTICANCER DRUGS
Biological
activity is the result of chemical compound's interaction with biological entity.
In clinical study biological entity is represented by human organism. In
preclinical testing it is the experimental animals (in vivo) and experimental
models (in vitro). Biological activity depends on peculiarities of compound
(structure and physico-chemical properties),
biological entity (species, sex, age, etc.), mode of treatment (dose, route,
etc.). Any biologically active compound reveals wide spectrum of different
effects. Some of them are useful in treatment of definite diseases but the
others cause various side and toxic effects. Total complex of activities
caused by the compound in biological entities is called the "biological
activity spectrum of the substance".Biological
activity spectrum of a compound presents every its activity despite of the
difference in essential conditions of its experimental determination. The
biological activity spectrum of PASS is designed according to the algorithm
specified below: For
the compound under prediction structural descriptors are generated. For each activity
the following values are calculated: uj = a i ArcSin{ri(2pij-1)},
u0j = a i ArcSin{ri(2pj-1)} sj = Sin(uj/m), s0j = Sin(u0j/m) Prj = (1+(sj-s0j)/(1-sjs0j))/2 Then the results are validated and
predicted., In case when the probabilities for more than 400 different
activities are estimated simultaneously, and the ideal training set should
include all referenced biologically active compounds from literature, the
best estimate of prediction's quality can be calculated by leave one out
cross validation. Each of the compounds is subsequently removed from the
training set and the prediction of its activity spectrum is carried out on
the basis of the remaining part of the training set. The result is compared
to the known activity of a compound, and the maximal error of prediction
(MEP) is calculated through the all compounds and activities. RESULTS
BIOLOGICAL ACTIVITY SPECTRUM OF THE ANTICANCER DRUGS
TAXOL
76 Substructure descriptors; 0 new. 45 Possible activities at Pa > 30% Pa Pi for Activity: 0,991 0,001 Antimitotic 0,982 0,001 Microtubule formation inhibitor 0,957 0,000 Antimitotic Taxane-like 0,945 0,001 Microtubule formation stimulant 0,850 0,004 Protein-arginine deiminase inhibitor 0,829 0,008 Antineoplastic 0,707 0,006 Antineoplastic enhancer 0,691 0,006 Radiosensitizer 0,652 0,014 CYP2C8 substrate 0,629 0,022 CYP3A substrate 0,661 0,106 Phosphatase inhibitor 0,529 0,001 Beta tubulin antagonist VINBLASTIN
87 Substructure descriptors; 0 new. 45 Possible activities at Pa > 30% Pa Pi for Activity: 0,949 0,002 Xenobiotic-transporting ATPase inhibitor 0,931 0,001 Antineoplastic alkaloid 0,912 0,003 Lactose synthase inhibitor 0,896 0,007 Antineoplastic 0,871 0,001 Tubulin antagonist 0,870 0,001 Antineoplastic (multiple myeloma) 0,713 0,027 Teratogen 0,692 0,007 Cytostatic 0,659 0,017 Embryotoxic 0,637 0,029 Toxic VINCRISTINE
88 Substructure descriptors; 0 new. 31 Possible activities at Pa > 30% Pa Pi for Activity: 0,941 0,001 Antineoplastic alkaloid 0,917 0,007 Antineoplastic 0,879 0,001 Tubulin antagonist 0,853 0,001 Antineoplastic (multiple myeloma) 0,816 0,003 Leukopoiesis inhibitor 0,802 0,006 Cytostatic 0,742 0,021 Teratogen 0,693 0,014 Embryotoxic 0,675 0,022 Toxic 0,579 0,003 Microtubule formation inhibitor TOPOTECAN
57 Substructure descriptors; 0 new. 64 Possible activities at Pa > 30% Pa Pi for Activity: 0,877 0,002 0,870 0,002 Topoisomerase I inhibitor 0,875 0,007 Antineoplastic 0,689 0,043 CYP2D16 substrate 0,626 0,010 Antiviral (Influenza) 0,614 0,002 Antineoplastic alkaloid 0,617 0,046 Apoptosis agonist 0,537 0,082 Magnesium
protoporphyrin IX monomethyl ester (oxidative) cyclase inhibitor 0,523 0,071 Immunomodulator 0,548 0,107 CYP3A1 substrate IRINOTECAN
66 Substructure descriptors; 0 new. 43 Possible activities at Pa > 30% Pa Pi for Activity: 0,894 0,007 Antineoplastic 0,840 0,002 0,810 0,002 Topoisomerase I inhibitor 0,796 0,002 Antineoplastic alkaloid 0,454 0,035 Antiviral (Influenza) 0,437 0,047 Alzheimer’s disease treatment 0,533 0,176 Nerve growth factor agonist 0,447 0,112 ®-Pantolactone dehydrogenase (flavin) inhibitor 0,484 0,157 Transplant rejection treatment 0,359 0,034 Tetrahydroxynaphthalene reductase inhibitor ETOPOSIDE 61 Substructure descriptors; 0 new. 72
Possible activities at Pa > 30% Pa Pi for Activity: 0,976 0,005 Hematotoxic 0,930 0,007 Antineoplastic 0,907 0,000 Antimitotic Podophyllotoxin-like 0,819 0,012 Pulmonary hypertension treatment 0,803 0,003 Topoisomerase I inhibitor 0,756 0,006 Carcinogenic, group 2A 0,725 0,008 CYP3A5 substrate 0,696 0,015 Emetic 0,683 0,003 0,666 0,002 Antimitotic TENIPOSIDE
67 Substructure descriptors; 0 new. 63 Possible activities at Pa > 30% Pa Pi for Activity: 0,942 0,006 Antineoplastic 0,902 0,004 Xenobiotic-transporting ATPase inhibitor 0,823 0,010 Cardiotoxic 0,782 0,016 Pulmonary hypertension treatment 0,726 0,004 Topoisomerase I inhibitor 0,717 0,007 Carcinogenic, group 2A 0,657 0,013 CYP2B6 substrate 0,606 0,012 CYP3A5 substrate 0,610 0,017 Beta-amylase inhibitor 0,598 0,027 Emetic DISCUSSION
Pa and Pi are the estimates of probability for the compound to be active and inactive respectively for each type of activity from the biological activity spectrum. Their values vary from 0.000 to 1.000. It is reasonably that only those types of activities may be revealed by the compound, which Pa > Pi and so they are put into the biological activity spectrum. Planning experiments and choosing the activities on which the compound has to be tested, one should have in mind the necessity of balancing between the novelty of pharmacological action and the risk to obtain negative result in experimental testing. Certainly, one will also take into account the particular interest in some kinds of activity, experimental facilities, etc. The accuracy of prediction is about 90%. CONCLUSION All
the seven drugs estimated show a good tendency to fight against the neoplastic cancer, also the drug Irinotecan is against Alzimers disease. Teniposide is
not as worthy as others as it is a cardiotoxic. Topotecan, Etaposide and Irinotecan are
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