Optimizing Drug Binding Affinity PDF

Optimizing Drug Binding Affinity  Drug Design: Optimizing Binding Interactions increase activity and reduce dose levels increase selectivity and reduce side effects Strategies: Vary alkyl substituents Vary aryl substituents Extension Chain extensions / contraction...

Optimizing Drug Binding Affinity  Drug Design: Optimizing Binding Interactions increase activity and reduce dose levels increase selectivity and reduce side effects Strategies: Vary alkyl substituents Vary aryl substituents Extension Chain extensions / contractions Ring expansions / contractions Ring variation Isosteres Simplification Rigidification  Vary Alkyl Substituents Rationale : Alkyl group in lead compound may interact with hydrophobic region in binding site Vary length and bulk of group to optimize interaction Patrick: Medicinal Chemistry  Vary Alkyl Substituents: Increasing selectivity Adrenaline β2 > β1 β1 > β2 Noradrenaline Salbutamol (Ventolin) (Anti-asthmatic) selective β2-receptor agonist Propranolol (β-Blocker) blocks the action of epinephrine and norepinephrine Patrick: Medicinal Chemistry on both β1- and β2-adrenergic receptors  Modulating lipophilicity antimicrobial activity HO OH R= Activity propyl 1.0 R butyl 4.2 pentyl 6.6 hexyl 10.2 heptyl 6.0 octyl 0.0 Fig. from Silvermann, pg.75  Chain Extension / Contraction Example : N-Phenethylmorphine Binding Binding group group Optimum chain length = 2 Patrick: Medicinal Chemistry  Ring Expansion / Contraction Rationale : To improve overlap of binding groups with their binding regions Hydrophobic regions Ring expansion R R RR Patrick: Medicinal Chemistry  Ring Variations Ring variation Improved selectivity Antifungal agent vs. fungal enzyme Nevirapine (antiviral agent) Additional binding group Patrick: Medicinal Chemistry  Extension - Extra Functional Groups ACE Inhibitors Patrick: Medicinal Chemistry  Simplification Rationale : Lead compounds from natural sources are often complex and difficult to synthesize Simplifying the molecule makes synthesis of analogues easier, quicker and cheaper Simpler structures may fit binding site easier and increase activity Simpler structures may be more selective and less toxic if excess functional groups removed Remove excess rings Remove asymmetric centres Patrick: Medicinal Chemistry Example Asperlicin - CCK antagonist Devazepide Possible lead for treating panic attacks Excess rings removed Disadvantages: Oversimplification may result in decreased activity and selectivity Simpler molecules have more conformations More likely to interact with more than one target binding site. Patrick: Medicinal Chemistry  Rigidification Rationale : Endogenous lead compounds often simple and flexible (e.g. adrenaline) Fit several targets due to different active conformations (e.g. adrenergic receptor types and subtypes) Rigidify molecule to limit conformations - conformational restraint Increases activity (more chance of desired active conformation) Increases selectivity (less chance of undesired active conformations) Disadvantage: Molecule more complex and may be more difficult to synthesize Rigidification Patrick: Medicinal Chemistry  Methods - Introduce rings Bonds within ring systems are locked and cannot rotate freely Test rigid structures to see which ones have retained active conformation Patrick: Medicinal Chemistry  Methods - Introduce rigid functional groups Combretastatin (anticancer agent) Rotatable bond Less active More active Patrick: Medicinal Chemistry  Methods - Steric Blockers Introduce steric block Flexible side chain Introduce steric block Coplanarity allowed Orthogonal rings preferred Patrick: Medicinal Chemistry  Steric Blockers Serotonin antagonist Introduce methyl group Steric clash Increase in activity Active conformation retained Patrick: Medicinal Chemistry  Isosterism in Drugs Often used by pharmaceutical companies Isosteric replacement may result in drugs having similar, opposite or different biological activity: there are no general rules which will predict if activity will increase or decrease Isosteric replacement of the bridge connecting groups necessary for activity and is itself not essential, may result a graduation of similar activity When the isosteric replacement involves a part of the molecule essential for an interaction with a receptor, loss of activity or antagonism may result Commonly encountered isosteres include the following: –O– –S– –NH– –CH2– –CH=CH– Another common set of isosteres are the aromatic rings; phenyl, pyridyl, thiophene, furan, and pyrrole; Lima and Barreiro (2005). Bioisosterism: a useful strategy for molecular modification and drug design. Curr. Med. Chem. 2005. 12, 23-49.  Isosteres and Bio-isosteres Rationale (Isosteres) : Replace a functional group with a group of same valency (isostere) e.g. OH replaced by SH, NH2, CH3 or O replaced by S, NH, CH2 Leads to more controlled changes in steric/electronic properties May affect binding and / or stability Rationale (Bio-isosteres) : Replace a functional group with another group which retains the same biological activity Not necessarily the same valency  Why making isosteres/bioisosteres? a drug candidate is already available but.. improve potency of the drug enhance selectivity change lipophilicity/hydrophilicity reduce metabolism/ increase metabolism eliminate or modify toxic metabolites create new intellectual properties  Classical Isotere Groups and Atoms 1. Univalent atoms and groups a. CH3 NH2 OH F Cl b. Cl PH2 SH c. Br i-Pr d. I t-Bu 2. Bivalent atoms and groups CH2 NH O S Se a. b. COCH2R CONHR CO2R COSR 3. Trivalent atoms and groups a. CH N b. P As 4. Tetravalent atoms a. C Si b. C N P 5. Ring equivalents a. CH CH S (e.g., benzene, thiophene) b. CH N (e.g., benzene, pyridine) c. O S CH2 NH (e.g., tetrahydrofuran, tetrahydrothiophene, cyclopentane, pyrrolidine) from: Organic Chemistry of Drug Design and Drug Action, Silverman & Holladay  Non Classical Isosteres As time progressed the definition of isosterism was broadened to include functional groups, such as O and NH (amide and amidine), cyclic/acyclic etc. Amide Amidine NCI do not have the same number of atoms and do not fit the steric and electronic rules Friedman (1951) introduced the term Bioisostere to fit the broadest definition for isosteres: This definition includes all isosteres that produce similar biological activity Non-Classical Isosteres from: Organic Chemistry of Drug Design and Drug Action, Silverman & Holladay  Replacement of H by 2H least disturbing replacement D is slightly less hydrophobic than H the molar volume is slightly smaller C-D bonds are shorter D can be introduced to increase metabolic stability increased metabolic stability Halogens (Fluorine) in Pharmaceutical Products O O O H OH OH O N F 6 N OH N COO- HCl H F3C 1/2 Ca2+ N N HN HCl F Prozac Lipitor Ciprobay anti-depressant cholesterol-lowering antibiotic 20% of all drugs are fluorinated compounds!  Fluorination Reagents SF3 SF3 N N nucleophilic N N F F DAST DFI Deoxofluor Cl F N+ N N+ 2BF4 - S S electrophilic F O O Selectfluor NFSI F F reagents to F Si Si N CF3 introduce CF 3 O O Ruppert-Prakash Trifluoroacetamide Properties of Fluor in Organic Molecules Fluor enhances metabolic stability by lowering the suscep- tibility of nearby moieties to cytochrome P450 enzymatic oxidation. F-C bonds are extremely stable, as well as adjacent C-C bonds Fluor can serve as bioisotere of a C-O bond, C=CHF for the peptide bond, the C-CF3 fragment for a C=O group, C-F for C- OH and C-OMe. Substitution of H by F may completely alter conformational preferences The basicity of adjacent N centers can be lowered, so that compounds tend to be more neutral and hence bioavailability is increased Replacing H by F in general increases lipophilicity of the compound Müller et al, Science 317, 2007, 1881-86 Fluor is not a good H-bond acceptor, because F is not polarizable However, the C-F dipole undergoes multipolar interactions C-F bonds pointing into polar environments reduce binding affinity C-F bonds avoid point to C=O groups C-F groups interact with C=O group in an orthogonal fashion C-F groups interact with guanidinium groups of Arg residues Introduction of Fluor may dramatically alter the binding mode Metabolic stabilization by introducing F Scheme 1. Development of Ezetimibe (SCH58235) by optimization of the lead SCH48461.[12,13] As part of the optimization, two metabolically labile sites are blocked by flu- orine substituents. Metabolic destablization by removing F Böhm, ChemBioChem 2004, 5, 637  Fluor substitution alters the basicity of adjacent N centers A B F Tyr60A P pocket R2 R3 R D pocket 4 HN O Asn98 Trp60D H H R5 NH2 HO N N HN O H O O R1 O F HO O NH2 H NH H N Ser195 X: HCl N N NH2 HN H Oxyanion O Trp215 hole H2O Compound R1 R2 R3 R4 R5 pK a (±) -1 H H H H H 7.0 O H O Gly219 N H (±) -2 X H H H H 4.5 N H N H N + (+) -3 X F H H H 3.4 Gly216 H H (+) -4 X H F H H 3.3 (+) -5 X H H F H 3.3 (+) -6 X H H H F 3.3 - O O S1 pocket (+) -7 X OH H H H 4.1 (+) -8 X OMe H H H 3.7 Asp189 (+) -9 X F F H H