Computer Aided Molecular Design

Computer Aided Molecular Design

Computer Aided Molecular Design A Strategy for Meeting the Challenges We Face An Organized Guide Build Chemical Insight Discover new molecules Predict their properties Working at the Intersection Structural Biology Biochemistry Medicinal Chemistry Toxicology Pharmacology Biophysical Chemistry Information Technology Structural Biology Fastest growing

area of biology Protein and nucleic acid structure and function How proteins control living processes Medicinal Chemistry Organic Chemistry Applied to disease Example: design new enzyme inhibitor drugs doxorubicin (anti-cancer) Pharmacology

Biochemistry of Human Disease Different from Pharmacy: distribution of pharmaceuticals, drug delivery systems New Ideas From Nature Natural Products Chemistry Chemical Ecology During the next two decades: the major activity in organismal biology

Examples: penicillin, taxol (anti-cancer) Working at the Intersection Structural Biology Biochemistry Medicinal Chemistry Toxicology Pharmacology Biophysical Chemistry Information Technology Principles Structure-Function Relationships Binding Step 1: Biochemical Mechanism Step 2: Understand and control macromolecular binding

Binding Binding interactions are how nature controls processes in living cells Enzyme-substrate binding leads to catalysis Protein-nucleic acid binding controls protein synthesis Principles Structure-Function Relationships Binding Understand and control binding ->disease

Molecular Recognition How do enzymes recognize and bind the proper substrates Guest-Host Chemistry Molecular Recognition in Cyclodextrins Molecular Recognition Hydrogen bonding interactions (salt bridges) Charge-charge Dipole-dipole interactions (aromatic)

Hydrophobic (like dissolves like) H Hosts: cyclodextrin OH O HO O OH O HO OH OH

O O HO HO OH O O HO O HO HO HO O OH

HO HO HO O O HO O HO HO O OH O Hexasulfo-calix[6]arenes O O S

O O O O S S O OH O OH OH OH

OH OH O O O O S S O O O S O O O Molecular Design Originated in Drug Design

Agricultural, Veterinary, Human Health Guest - Host Chemistry Ligands for Inorganic Complexes Materials Science Polymer Chemistry Supramolecular Chemistry Semi-conductors, nonlinear phenomena Information Technology Chemical Abstracts Service registered over one million new compounds last year Expected to increase every year Need to know the properties of all known compounds: pharmaceutical lead compounds environmental behavior Information Technology Store and Retrieve

Molecular Structures and Properties Efficient Retrieval Critical Step Multi-million $ industry Pharmaceutical Industry $830 million to bring a new drug to market Need to find accurate information Shorten time to market, minimize mistakes CAMD Computational techniques to guide chemical intuition Design new hosts or guests Enzyme inhibitors Clinical analytical reagents Catalysts CAMD Steps Determine Structure of Guest or Host Build a model of binding site

Search databases for new guests (or hosts) Dock new guests and binding sites Predict binding constants or activity Synthesize guests or hosts Structure Searches 2D Substructure searches 3D Substructure searches 3D Conformationally flexible searches cfs 2D Substructure Searches Functional groups Connectivity [F,Cl,Br,I]

Halogen substituted aromatic and a carboxyl group O O 2D Substructure Searches Cl Query: Cl O Halogen substituted aromatic and a carboxyl group O O

O N O O F O N O N N N N F

I O F O 3D Substructure Searches A Spatial Relationships Define ranges for distances and angles

Stored conformation O(s1) C(u) O(s1) 3.3 - 4.3 O 6.8 - 7.8 usually lowest energy 3.6 - 4.6 [O,S] A Conformationally Flexible Searches

Rotate around all freely rotatable bonds Many conformations Low energy penalty Get many more hits Guests adapt to hosts and Hosts adapt to guests Cl 3.2 O H Cl 4.3 O H

Conformationally Flexible Searches Cl 3.2 O H Cl 4.3 O H 6 Small energy penalty Steric Energy (kcal/mol) 5

4 3 2 1 0 0 60 120 180 240 Dihedral angle 300

360 Angiotensin Converting Enzyme Zn containing protease Converts Angiotensin I Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu -> Angiotensin II O Cl Raises blood pressure Vascular constriction Restricts flow to kidneys Diminishing fluid loss N N N

N N Losartan N Computer Aided Molecular Design Quantitative Structure Activity RelationshipsQSAR Quantitative Structure Property RelationshipsQSPR Introduction Uncover important factors in chemical reactivity Based on Hammett Relationships in Organic Chemistry Medicinal Chemistry Guest-Host Chemistry Environmental Chemistry CAMD

Determine Structure of Guest or Host Build a model of binding site Search databases for new guests (or hosts) Dock new guests and binding sites Predict binding constants or activity Synthesize guests or hosts Outline Hammett Relationships log P : Octanol-water partition coefficients uses in Pharmaceutical Chemistry uses in Environmental Chemistry uses in Chromatography Other Descriptors Multivariate Least Squares Nicotinic Agonists - Neurobiology Acetylcholine Esterase

Neurotransmitter recycling Design drug that acts like nicotine Acetylcholine Esterase RCSB Protein Data Bank (PDB) Human diseasemolecular biology databases SWISS-PROT OMIM GenBank MEDLINE Acetylcholine Esterase CH3 H3C + N

CH3 CH3 O CH2 CH2 O C CH3 H3C +N CH2 CH2 O H O +

CH3 +HO 2 N Nicotine N H + O C CH3 + +

H Hammett Relationships pKa of benzoic acids Effect of electron withdrawing and donating groups based on rG = - RT ln Keq pKa Substituted Benzoic Acids log Ka - log KaH = K aH is the reference compound1 log Ka unsubstituted 0.8 O

O H -1 R1 0.6 0.4 0.2 0 -0.5 -0.2 0 -0.4 -0.6 -0.8 0.5 1 sigma Hammett Constants

Group -NH 2 -OH -OCH3 -CH 3 -H -F -Cl -COOH -CN -NO 2 p m -0.57 -0.38 -0.28 -0.14 0 0.15 0.24

0.44 0.70 0.81 -0.09 0.13 0.10 -0.06 0 0.34 0.37 0.35 0.62 0.71 Sigma-rho plots One application of QSPR Activity = + constant Y = mx + b descriptor : slope

Growth Inhibition for Hamster Ovary Cancer Cells N (CH2 CH2 Cl)2 R 1.5 -NH3+ y = -2.5 1 2 R = 0.97 0.5 log(1/IC50) - 0.21

0 -1 -0.5 -0.5 0 0.5 1 -1 -1.5 -NO2 -2 -2.5

Octanol-Water Partition Coefficients P = C(octanol) C(water) log P like rG = - RT ln Keq Hydrophobic hydrophilic character P increases then more hydrophobic Octanol H2O QSAR and log P

Isonarcotic Activity of Esters, Alcohols, Ketones, and Ethers with Tadpoles Compound CH3 OH C2H5OH CH3 COCH3 (CH3) 2CHOH (CH3) 3COH CH3 CH2 CH2OH CH3 COOCH3 C2H5COCH3 HCOOC 2 H5 C2H5COC2H5 (CH3) 2C(C2H5 )OH CH3 (CH2) 3OH (CH3) 2CHCH2OH CH3 COOC2 H5 C2H5COC2H5 CH3 (CH2) 4OH CH3 CH2 CH2COCH3 CH3 COOCH2C2 H5 C2H5COOC2H5

(CH3) 2CHCOOC 2 H5 log(1/C) 0.30 0.50 0.65 0.90 0.90 1.00 1.10 1.10 1.20 1.20 1.20 1.40 1.40 1.50 1.50 1.60 1.70 2.00 2.00

2.20 log P -1.27 -0.75 -0.73 -0.36 0.07 -0.23 -0.38 -0.27 -0.38 0.59 0.59 0.29 0.16 0.14 0.31 0.81 0.31 0.66 0.66 1.05

QSAR and log P Isonarcotic Activity of Esters, Alcohols, Ketones, and Ethers with Tadpoles log(1/C) 2.5 y = 0.7315x + 1.2211 2 R2 = 0.7767 R = 0.881 1.5 n = 20 1 0.5 0 -2 -1 0

log P 1 2 Isonarcotic Activity of Esters, Alcohols, Ketones, and Ethers with Tadpoles log(1/C) = 0.869 log P + 1.242 n = 28 r = 0.965 subset of alcohols: log(1/C) = 1.49 log P - 0.10 (log P)2 + 0.50 n = 10 r = 0.995

log P hydrophobic benzene 2.13 pentanol 0.81 n-propanol -0.23 isopropanol -0.36 ethanol -.75 methanol -1.27 hydrophillic butylamine 0.85 pyridine 0.64 diethylamine 0.45 imidazole -0.08 phenylalanine -1.38 tetraethylammonium iodide -2.82 alanine -2.85 Estimating log P

M (aq) > M (octanol) PG = -RT ln P M (aq) > M (g) M (octanol) > M (g) PG = desolG(aq) desolG(octanol) PG = Fh2o - Foct log P = (1/2.303RT) Fh2o - Foct

desolG(aq) 1/2.303RT = 0.735 desolG(octanol) Solvent-Solute Interaction desolG(aq) = Fh2o Free Energy of desolvation in water desolG(aq) = -RT ln KHenrys desolG(octanol) = Foct Free Energy of desolvation in octanol Descriptors Molar Volume, Vm Surface area Rotatable Bonds, Rotbonds, b_rotN

Atomic Polarizability, Apol Ease of distortion of electron clouds sum of Van der Waals A coefficients Molecular Refractivity, MR size and polarizability local non-lipophilic interactions Atomic Polarizability, Apol Atomic Polarizability Ease of distortion of electron clouds sum of Van der Waals A coefficients A B EVdW,ij = - r 6 + r 12 ij ij

Molecular Refractivity, MR Molecular Refractivity, MR size and polarizability local non-lipophilic interactions Lorentz-Lorentz equation: 2 (n - 1) MW MR = (n2 + 2) d Group Additive Properties, GAPs Substituent Volume (SA) -H 1.48 -CH3

18.78 -CH2CH3 35.35 -CH2CH2CH3 51.99 -CH(CH3)2 51.33 -CH2CH2CH2CH3 68.63 -C(CH3)3 86.99 -C6H5 72.20 -F 7.05 -Cl 15.85 MR Rot Bonds 0.10 0 (reference) 0

0.57 0.56 0 1.03 1.02 1 1.5 1.55 2 1.5 1.53 1 1.96 2.13 3 1.96 1.98 1 2.54 1.96 1 0.10 0.14

0 0.60 0.71 0 Bioisosteres for carboxyl groups Substituent pKa MR -COOH 4.2 -0.32 6.9

-4.36 6.0 -0.48 15.6 -3.55 14.6 -4.76 ~10 -COOH N N N N 4.5

(tetrazols) N N N N -SO3- (sulfonates) -SO2NH2 (sulfonamides) 10 -1.82 12.3 -P(O)(OH)2

(phosphonic acids) 1.42 -1.59 12.6

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