Drug Design & Drug-Target Interactions PDF

DRUG DESIGN & DRUG-TARGET INTERACTIONS Identification of the pharmacophore Target-orientated drug design Pharmacokinetic drug design Testing for drug metabolites Manufacturing – synthetic issues Toxicity testing Clinical Trials Identification of the Pharmacophore Once we establis...

DRUG DESIGN & DRUG-TARGET INTERACTIONS Identification of the pharmacophore Target-orientated drug design Pharmacokinetic drug design Testing for drug metabolites Manufacturing – synthetic issues Toxicity testing Clinical Trials Identification of the Pharmacophore Once we establish which groups are important for activity through SAR, we can identify the pharmacophore. The pharmacophore summarizes: – the important functional groups which are required for activity. – their relative positions in space with respect to each other. This allows simplification of often very complex lead compounds arising from natural products. This was successfully employed with the alkaloid cocaine. CO2Me N N Me O O O O Cocaine: Procaine Local anaesthetic (Novocaine)  Target-Orientated Drug Design Once you know the pharmacophore, why make analogues? To increase activity To reduce side-effects To provide easy & efficient administration Ease of synthesis The strategies below are used to improve the interactions between drug & target: – Variation of substituents – Extension of the structure – Chain extensions/contractions – Ring variation – Ring fusions – Isosteres – Rigidification of the structure  Target-Orientated Drug Design Variation of Substituents H N CH3 Steric O H O Block N CH3 Fit Y Y Binding region Para substitution Meta substitution Extension of the Structure Vacant hydrophobic pocket CH3 CH3 O O N N H H O O CO2 O O CO2 Binding site Binding site  Target-Orientated Drug Design Chain extensions/contractions Strong interaction Weak interaction NH2 NH2 OH OH Binding regions Recepto Recepto r r Ring variations O O O HN HN HN N N N N N N N N CO2tBu CO2tBu Lead compound Additional Nevirapine binding group -antiviral  Target-Orientated Drug Design Ring fusions OH H OH H HO N N CH3 CH3 CH3 HO Adrenaline Pronethalol a & b receptors b receptor only Isosteres – atoms or groups with the same valency. E.g. SH, NH2, CH3 are isosteres of OH. Size is similar but polarity, electronic distribution and bonding are different. OH H SH H N N N N N N N hypoxanthine 6-mercaptopurine- immunosuppressive  Target-Orientated Drug Design Rigidification – “locks” a drug into a more rigid conformation cannot take up other shapes. Consequently activity increases & side-effects decrease. Rotatable bonds H H NH2Me CO2H O O NH2Me NH2 O H H HN N H Bond rotation Flexible guanidine chain O Ar Diazepine ring system Fixed bonds NH2 H HO2C HN O O H NHMe N N O CH3 NR rigid rigid  Pharmacokinetic Design A drug’s success in reaching its target depends upon its physical, chemical, & metabolic stability, including its hydrophilic/hydrophobic character, ionization and size. Metabolic Stability – Attack by metabolic enzymes (liver) – Polar drugs are quickly excreted by the kidneys – Non-polar drugs get converted into more polar ones through metabolism Phase I – oxidation (P450 enzymes), reduction, hydrolysis Phase II – conjugation reactions (liver) polar molecule attached  Testing For Drug Metabolites Drugs are tested on animals & humans to examine which metabolites are formed. Ideally only inactive metabolites are formed which are quickly excreted. It is common to find that the drug administered is inactive, but is converted to an active metabolite in vivo. If however toxic metabolites are formed, this may stop a study going forward. Manufacturing – Synthetic Issues The most active drug may not be the one you end up manufacturing. Points to consider: – Ease of synthesis- Yield Number of steps Experimental procedure (stereochemistry – separation) Purification – Economic costs – Safety  Toxicity Testing Safety assessment In vitro – Engineered cell cultures In vivo – Lab animals (trangenic mice) LD50 – lethal dose required to kill 50% of subjects – Fails to pick up non lethal or long-term toxicity TD50 – toxic dose to 50% of subjects ED50 – effective dose to 50% of subjects Therapeutic window – dosage of a medication between effective dose and the amount that gives more adverse effects than desired effects  Thalidomide – the drug that should have failed Racemic mixture used as a strong sedative with antiemetic properties used in the late 1950’s. R-enantiomer S-enantiomer O O H H N N O Optical Isomers O O N O O N O H H Right-hand: one receptor site Left-hand: different receptor site R-enantiomer effective against morning sickness. S-enantiomer is teratogenic (inserts into DNA) causing birth defects. The R-enantiomer isomerizes to the S-enantiomer in vivo. Withdrawn in 1961. 10,000 – 20,000 possible victims. Now being used again for multiple myeloma and leprosy (antiangiogenic)  Clinical Trials This is where most drugs fail! Phase I – Generally few subjects involved – Usually healthy volunteers (sometimes patients) – Test potency, pharmacokinetics, side-effects Phase II – Small group of patients – Tests side-effects & dosage levels Phase III – Large sample – Comparative to other treatments – Placebo affect – Double-blind technique – Leads to licensing & marketing Phase IV – Now on the market & can be prescibed – Still monitored for effectiveness & side-effects