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1. 2. 3. 4. Identification of pharmacophore Functional group modification Structure-Activity relationship Structure modification to increase potency and therapeutic index
homologation chain branching ring-chain transformation bioisosterism
1. Identification of pharmacophore
Pharmacophore: the relevant groups on a molecule that interact with a receptor and are responsible for the biological activity
----these groups are in direct contact with the enzyme or receptor ----keep the pharmacophore chemically and conformationally unchanged, the other parts of the molecule can be extensively modified without hurting the biological activity
Chlorothiazide --antihypertensive agent (good quality) --strong diuretic effect (bad side effects)
3. Structure-Activity relationship
There are many structural features for any active compounds. Some of these features are important for the activity and the others are not.
(1) NH2 and sulfonyl (R) should be para (2) NH2 should be unsubstituted (3) Benzene ring should not be replaced by other ring systems. No additional substitution (4) R could be variable (5) N-monosubstitution (R=SO2NHR) results in potency increase (6) N-disubstitution (R=SO2NHR) results in inactive compounds
R=
A. Homologation: a homologous series is a group of compounds that differ by a constant unit, usually CH2
B. C.
Affects (1) lipophilicity, (2) interaction with the enzyme or receptor. It could increase or decrease drug potency and therapeutic index
Branching decrease lipophilicity when lipophilicity is major factor in activity, Branching generally decreases the potency
Methdilazine
Antimalarial drug
X = H, R = CH2CH(CH3)CH2N(CH3)2
Trimeprazine
D. Bioisosterism Bioisosteres are substituents or groups that have chemical or physical similarities, And which produce broadly similar biological properties. Bioisosterism is a very successful approach to lead optimization. By making a bioisosteric replacement, the potency is basically unchanged but many other parameters of the drug molecule will be changed: size, shape, electronic distribution, lipid solubility, water solubility, pKa, chemical reactivity, and hydrogen bonding, etc. It can be used to have the effects of : a. Structure b. Receptor interaction c. Pharmacokinetics d. Metabolism
E. Quantitative structure-activity relationships (QSAR-rational drug design) The concept of quantitative drug design is based on the fact that the biological properties of a compound are a function of its physicochemical parameters. Physical properties: solubility, lipophilicity, electronic effects, ionization, stereochemistry, etc.
Factors affecting : Inductive / resonance effect Involvement of H-bond Steric effects Conformational effects
Example
Molar refractivity: another parameter to indicate steric effect It is defined by the Lorentz-Lorenz equation
Free SM Jr. Wilson JW, 1964. J. Med. Chem. 7, 395 Blankley CJ, 1983. In Quantitative structure-activity relationships of drugs (Topliss, JG Ed.) Chap.1. Academic Press, New York Fujita T, Ban T. 1971, J. Med. Chem. 14, 148
3.
Topliss analysis
A nonmathematical, nonstatistical, and noncomputerized application of Hansch principles. It is an approach for the efficient optimization of the potency of a lead compound with minimization of the number of compounds needed to be synthesized. It relies heavily on and values and a much less degree the steric effects. Only prerequisite for this method is that the lead compound must contain an unfused Benzene ring. 40-50% drugs are substituted benzenes. Topliss, JG, 1972. J. Med. Chem. 15, 1006 Topliss, JG, 1977. J. Med. Chem. 20, 463
Although few X-ray structures, topography of an unknown receptor could be deduced from Related known receptor structures:
Carlson GM et al. 1986. J. Theor. Biol. 119, 107 Blaney et al. 1982. J. Med. Chem. 25, 785
Also, a technique is available to identify the pharmacophore geometry of an unknown receptor from data of known ligand binding studies:
Marshall GR et al. 1981. Mol. Pharmacol. 19, 307 Marshall GR et al. 1980. Annu. Rep. Med. Chem. 15, 267 Marshall GR. 1985. Ann. N. Y. Acad. Sci. 439, 162