JBBs

Research Interests: Coordination Chemistry Drug Design and Development Electrochemical Synthesis and Characterization Spectroscopic Analysis (UV-VIS, IR, NMR, MS) Molecular Modeling Microwave chemistry Green Chemistry

BLOCKED An HMG-domain protein (HMGB1; domain A shown as gray ribbon) inserts a phenyl group (yellow) into the groove created when cisplatin (platinum shown in red) forms a complex with DNA, causing it to bend.

Antitumor Ruthenium complex

RuX3.xH2O + L RuX3L3 + xH2O Biologically safe and relevant Potential anti-tumour agent Biodegradable polymer

Oligomers of Ascorbic Acid and Glycerol

[RuBr6]-3

[RuBr5(RCN)]-2

[RuBr4(RCN)2]-1

[RuBr3(RCN)3]

[RuBr2(RCN)4]+1

[RuBr (RCN)5]+2

RCN (*)

Spectro-Electrochemistry
MLCT
RuIII (d)

RuII (d)

LMCT

Br ()

Billones, 1999

Fourier Transform Infra-red (FTIR) Spectroscopy

NMR Spectroscopy

1H-NMR

Spectrum

Computational chemistry (also called molecular modeling) -is a set of techniques for investigating chemical problems on a computer. Questions commonly investigated computationally are: Molecular geometry: The shapes of molecules bond lengths, angles, and dihedrals.

Energies of molecules and transition states: This tells us which isomer is favored at equilibrium, and (from transition state and reactant energies) how fast a reaction should go.

Mechanism of peptide bond synthesis on the ribosome

Reaction energetics and product structure (a) Reaction free energy diagram obtained for the uncatalyzed reference reaction in water (upper curve) and for the ribosome reaction (lower curve). (b) Calculated structure of the bound product (cyan) superimposed on the experimental structure of Cpuromycincaproic acidbiotin (C-pmn-pcb) in the ribosomal A-site (13).

Chemical reactivity For example, knowing where the electrons are concentrated (nucleophilic sites) and where they want to go (electrophilic sites) enables us to predict where various kinds of reagents will attack a molecule.

HOMO-LUMO interaction is highly favored.

IR, UV, and NMR spectra These can be calculated, and if the molecule is unknown, someone trying to make it knows what to look for.

Superposition of experimental and calculated spectra for flavone. Blue=experimental, red=calculated, green=oscilator strength

A Gaussian calculation of the methanol dimer showing the calculated IR spectrum and the normal coordinates of the most intense mode.

The interaction of a substrate with an enzyme Seeing how a molecule fits into the active site of an enzyme is one approach to designing better drugs.

The physical properties of substances These depend on the properties of individual molecules and on how the molecules interact in the bulk material.

For example, the strength and melting point of a biomolecule (e.g. fatty acids) depend on how well the molecules fit together and on how strong the forces between them are.

acetone

CH stretch CO stretch

generates IR spectrum

acetaldehyde

promotion of nonbonding electrons

generates UV-Vis spectrum

1H-NMR

methyl protons

13C-NMR

carbonyl C

methyl C

Molecular Modeling
I. Computational Tools A. Molecular Mechanics B. Semi-Empirical C. Ab initio D. DFT II. Graphical Models A. Molecular Orbitals B. Isodensity Surfaces C. Molecular Electrostatic Potential D. Mapped Surfaces E. Other Outputs E. Molecular Dynamics F. Langevin Dynamics G. Monte Carlo III. Selected Experiments A. Molecular Design of HIV RT Inhibitors B. DFT Study of Allicin C. QSAR of NSAIDs D. Design of Anti (Dengue)viral Agent E. Docking of Anti-TB

Draw molecules in 2D

Construct DNA, RNA or protein from residues

Use/display molecules from PDB files

Model Builder Approximate 3D structures

QSAR QSPR
Molecular and Langevin dynamics Monte Carlo

Single point Methods: MM QM

Geometry optimization MM QM

Vibrational analysis TS searching QM

Results:

Total energy of one configuration

A stable configuration

IR spectra transition state conformation

Simulation of changing molecular conformation with time and temperature, ensemble averaging

I. Computational Tools Molecular Mechanics Total energy of a molecule is described in terms of a sum of contributions arising from coordinate distortions (i.e. stretch, bend, torsion) and non-bonded interactions.

Etotal = Estretch + Ebend + Etorsion + Enon-bonded

Geometry optimization (energy minimization) variation of molecular coordinates to obtain the lowest E configuration.

A potential energy surface with identifications of its topological features.

A local minimum corresponds to a stable structure or conformer. Saddle point is important for elucidating reaction mechanism and chemical kinetics.

The landscape picture for DNA hairpin folding and melting. The freeenergy surface with multiple global minima depicts folded, collapsed (compact) intermediate, and single-stranded structures

Tube

Space-filling

Ball and Spoke

Wire

Molecular Orbital Models MO methods seek an approximate solution to deceptively simple-looking differential (Schrdinger) equation

H = E

Ab Initio or Hartree-Fock Self-Consistent Field (HFSCF) Methods Results from solution to Roothaan-Hall equations which are simplified Schrodinger equations.

*2p 2p 2p 2p 2s *2s *1s 1s 2p *2s 2s *1s 1s 2p 2p 2p

*2p

2p *2s 2s *1s 1s

In the broadest sense, molecular dynamics is concerned with molecular motion. Conformational transitions and local vibrations are the usual subjects of molecular dynamics studies. Newton's equation is used in the molecular dynamics formalism to simulate atomic motion:

The steps in molecular dynamics meaningfully represent the changes in atomic position, ri, over time (i.e. velocity).

Molecular dynamics basically involves calculation of the force on each atom, and from that information, the position of each atom throughout a specified period of time (ps). Softwares: AMBER, CHARMM, CHARMM/GAMESS, Discover, QUANTA/CHARMm, HYPERCHEM, and SYBYL.

Example of using MD to pull a sodium ion (large sphere) through the gramacidin A channel.

Molecular dynamics "snapshot" of water molecules (blue and white), sodium ions (purple), and methane molecules (yellow-brown) intercalated simultaneously between two layers of montmorillonite, a common clay mineral.

Site of electrophilic attack

Site of nucleophilic attack

MOLECULAR DESIGN OF NOVEL HIV REVERSE TRANSCRIPTASE INHIBITORS

Villavicencio, R.; BS Biochemistry Thesis, UP Manila 2006. Best Thesis

Electrostatic potential of compound 7

Villavicencio, R; Billones, J. Phil. J. Sci. 2009, 138 (1): 105-113

Surface model of wild-type reverse transcriptase in complex with 7

Sites of Metabolism of Compound 7

Hydrophobic and aromatic interactions of NR8 with wild- type reverse transcriptase

DFT Study of Allicin

Charge=(-1) 8.0 6.0 4.0 2.0
Charge=(-1)
8.0

major component of garlic

MO E-Level Diagram of Allicin

Charge=(0) Charge=(+1)

Charge=(0)

Charge=(+1)

6.0

4.0

0.0

2.0

0.0

-2.0

-4.0

-6.0

-8.0

The energy of allicin decreases with upon oxidation indicates antioxidant activity

Energy (eV)

-10.0

-12.0

-14.0

Energy (eV)

-2.0 -4.0 -6.0 -8.0 -10.0 -12.0 -14.0

Calculated Electronic Properties of Allicin

Table 1. Some electronic properties calculated for Allicin using DFT/RB3LYP method. The molecular charges used (-1, 0, +1) are indicated in parenthesis. Compounds ET (keV) EHOMO (eV) ESOMO (eV) ELUMO (eV) Allicin (-) -30.1014 0.80525 -0.29599 3.43945 Allicin (0) -30.1004 -6.34505 -1.46533 Allicin (+) -30.0921 -11.87110 -11.20151 -7.54988 -2 1 eV = 3.674 x 10 hartree (au)

Theoretical UV-Vis Spectrum of Allicin

nS *S Allicin (0)

nS *S C *S

Allicin (-1)

Quantitative Structure-Activity Relationship (QSAR) Study of Cyclooxygenase-2 (COX-2) Inhibitors

(NIH Project: 023-2002)
Billones, J; Buenaobra, S. Phil J. Sci. 2010 (submitted for publication)

The Cyclooxygenase Enzyme (Prostaglandin synthase)

Families of Tricyclic COX-2 Inhibitors

R1 R2

R1

R2

R1

R2

N R3 R4

N N R3

A (Pyrrole)
20
R1 R2

B (Imidazole)
114
R1 R2

C (Cyclopentene)
34
R1 R2

R3

R3

N N
R3

R4 R3

D (Benzene)
40
R1 R2

E (Pyrazole)
64
R1

F (Spiroalkene)
28
R1 R2

R2

R3

G (Spiroheptadiene)
2

H (Isoxazole)
2

I (Thiophene)
1

Model 1 (3-D Parameters)

-log IC50 = -13.19 C1pc (0.85) + 15.48 C4pc (1.35) - 9.10 C8pc (0.90) + 5.46 (0.14) ( n = 150 r = 0.933 r2 = 0.870, s = 0.363 F = 325.06 q = 0.930 q2 = 0.865) Inhibitory activity of tricyclic compounds is enhanced by: decreasing the partial charges on carbons 1 and 8 (C1pc and C8pc - accounts for 78% in variability) and increasing the partial charge on carbon 4 (C4pc)
Electron density (accessibility) on C1 and C8 should increase and that on C4 should decrease for improved activity.

Validation of Model 1 (LOO Method)

Predicted Values versus Experimental Values for the Validation of Model 1
10.00

8.00

pIC50(calc)

6.00

q = 0.93 q2 = 0.87
4.00 4.00

5.00

6.00

7.00

8.00

9.00

10.00

pIC50(exptl)

Lowest Unoccupied Molecular Orbital (LUMO) Isosurface of Compound 294

C1

C8

Gmin is correlated with C1pc, C8pc, and ELUMO SHother and SHCsat are correlated with C8pc and ELUMO

Representative Structure of COX-2 Inhibitor

sulfonyl
Must have e-releasing or moderately weak e-withdrawing substituent

C4

NH2, Br or CN

A
Must be more positive

B
C1 C8

Must be enriched

C
Must be more negative

Compound 294

Activity of COX-2 Inhibitors

10
Proposed Inhibitors

Valdecoxib

pIC50
6
Celecoxib

4 Inhibitors A F B G C H D I E Prop

Design of Dengue NS3 Protease Peptide Inhibitors

Panibe, J., Billones, J. 2008 BS Biochem Thesis, UP Manila

DEN1 NS3

DEN2 NS3

DEN3 NS3

DEN4 NS3

DEN1 NS2B-NS3

DEN2 NS2B-NS3

DEN3 NS2B-NS3

DEN4 NS2B-NS3

Figure 22a. Inhibitor H docked to the four DEN NS3 serine protease displayed as a molecular surface

Molecular Docking of Curcumin Analogues to Panthotenate Synthase

Submitted for Publication: Yang, C, Billones J.Phil. J. Sci. 2010

Electrostatic surface map of Panthotenate synthatase with bound curcumin analogue

Hydrogen bonding and hydrophobic interactions of cucrcumin analogue with PS.

Green Chemistry
- lso called sustainable chemistry " a - esign of products and processes that reduce or eliminate the d use and generation of hazardous substances" The 12 principles:"
1. Prevent waste"
Design chemical syntheses to prevent waste, leaving no waste to treat or clean up."

2. 3.

Design safer chemicals and products"

Design chemical products to be fully effective, yet have little or no toxicity."

Design less hazardous chemical syntheses"

Design syntheses to use and generate substances with little or no toxicity to humans and the environment."

4.

Use renewable feedstock"

Use raw materials and feedstock that are renewable rather than depleting. Renewable feedstock are often made from agricultural products or are the wastes of other processes; depleting feedstock are made from fossil fuels (petroleum, natural gas, or coal) or are mined."

5.
"

Use catalysts, not stoichiometric reagents"

Minimize waste by using catalytic reactions. Catalysts are used in small amounts and can carry out a single reaction many times. They are preferable to stoichiometric reagents, which are used in excess and work only once."

6.
"

Avoid chemical derivatives: "

Avoid using blocking or protecting groups or any temporary modications if possible. Derivatives use additional reagents and generate waste."

7.

Maximize atom economy"

Design syntheses so that the nal product contains the maximum proportion of the starting materials. There should be few, if any, wasted atoms."

8.
"

Use safer solvents and reaction conditions"

Avoid using solvents, separation agents, or other auxiliary chemicals. If these chemicals are necessary, use innocuous chemicals. If a solvent is necessary, water is a good medium as well as certain eco-friendly solvents that do not contribute to smog formation or destroy the ozone."

9. Increase energy efciency"

" Run chemical reactions at ambient temperature and pressure whenever possible."

10. Design chemicals and products to degrade after use"

" Design chemical products to break down to innocuous substances after use so that they do not accumulate in the environment."

11. Analyze in real time to prevent pollution"

" Include in-process real-time monitoring and control during syntheses to minimize or eliminate the formation of byproducts."

12. Minimize the potential for accidents"

" Design chemicals and their forms (solid, liquid, or gas) to minimize the potential for chemical accidents including explosions, res, and releases to the environment."

Key Developments:" 1. Green solvent - CO2, water, solventless" 2. Green reactions" - clean oxidation with H2O2" - use of H2 in asymmetric synthesis"

Uncatalyzed and Solventless Microwave Synthesis of Copolymer of Urea and Glycerol by: Bonifacio 2009

Microwave, 30 s

Urea-Glycerol-Urea-Glycereol-Urea-Glycerol-Urea-Glycerol-Urea-Glycerol

Interesting Topics on Microwave Chemistry Negative Effect of microwave heating on food and supplements Isomerization of cis-fatty acid (in cooking oil) to trans-fatty Acid on Microwave Heating Effect of Microwave Heating on the Properties of Water and Aqueous Mixtures (with coffee, sugar, choco, etc) Evaluation of Antioxidant Activity of Vitamins C and E After Microwave Irradiation Positive Effect of microwave heating in organic synthesis Microwave Synthesis: New Methods for Old Chemistry Uncatalyzed/Solventless Common Organic Reaction under Microwave Condition

Interesting Topics on Synthesis Synthesis, Characterization and Biological Activity of MetalLigand Complex Synthesis and Characterization of Biodegradable Polymers and Application in Drug Delivery System Synthesis and Characterization of Poly-Vitamins and MineralVitamins Complexes and Application in Controlled Release Drugs and Supplements Interesting Topics on Analytical Chemistry Development of Fast, On-Site Analytical Methods for Commonly Analyzed Biological Substances (e.g. glucose, creatinine, cholesterol, K+, etc)

Interesting Topics on Computational Bio-Chem Mechanism of A very interesting but poorly understood chem or biochem reaction Molecular Docking of Known Compounds to Identified Drug Targets QSAR Studies of Known Compounds and Developments of Next Generation Drug Candidates De Novo Drug Design for A Very Relevant Target Theoretical Studies of as yet Unknown or Unconceived Materials especially Nanoparticles

Claude Louis Berthollet

Paris, 1778

Joseph Louis Gay-Lussac

Paris, 1800

Justus von Liebeg

Erlangen, 1822

Carl Schmidt
Geissen, 1844

Wilhelm Ostwald
Dorpat, 1875

Arthur Noyes
Leipzig, 1890

Donald Yost
Caltech, 1926

Donald Martin Jr.

Caltech, 1944

Richard Fenske
Iowa SU, 1961

Nenad Kostic
Univ Wisconsin, 1982

Eva Marie Ratilla

Iowa SU, 1990

Junie B. Billones
UP-Australian NU, 1999

2000: Abueva, EC (Best Thesis); Tecson, HDC; 2001: Labaclado, LM; Santos, MT (Best Thesis); Tongo, EA; 2002: Guintu, P (Best Thesis); Amarga, AM; Baltazar, RP; Jacobo, SM; Montales, T; Ortiz, E.; Pangilinan, MG; 2003: Yladia, JM; Lao, MH; Buenaobra, S. 2004: Benedicto, BM; Mendoza, CD; 2005: Catral, JM; Flores, ML; Herrera, MA; Quiocho G. Conquilla, J. 2006: Aranas MB; Go, Sheryll; Torres, G.; Baltazar D Villavicencio, RN (Best Thesis) 2007: Donado, Capellan C, Asa A, (Sandstig in progress) 2008: Panibe (2008 NAST Best Poster Health Sci), Enriquez, Ting, Suico, Sta. Clara, Laguitan, Ocampo 2010: Zaragoza, Sacramento, Cruz, Yang, Reyes, Bonifacio