JBB’s

Research Interests:

Coordination Chemistry

Drug Design and Development

Microwave chemistry

Electrochemical Synthesis and Characterization

Spectroscopic Analysis (UV-VIS, IR, NMR, MS)

Molecular Modeling

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

Oligomers of Ascorbic Acid and Glycerol

RuX3.xH2O + L → RuX3L3 + xH2O

Biologically safe and relevant

Potential anti-tumour agent

Biodegradable polymer

[RuBr6]-3

[RuBr5(RCN)]-2

[RuBr4(RCN)2]-1

[RuBr3(RCN)3]

[RuBr2(RCN)4]+1

[RuBr (RCN)5]+2

RuII (dπ)

RCN (π*)

RuIII (dπ)

Br (π)

MLCT

LMCT

Billones, 1999

Spectro-Electrochemistry

Fourier Transform Infra-red (FTIR) Spectroscopy

1H-NMR Spectrum

NMR Spectroscopy

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.

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

Energies of molecules and transition states:

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 b o u n d p r o d u c t ( c y a n ) s u p e r i m p o s e d o n t h e experimental structure of C-puromycin–caproic acid–biotin (C-pmn-pcb) in the ribosomal A-site (13).

Mechanism of peptide bond synthesis on the ribosome

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.

Chemical reactivity

HOMO-LUMO interaction is highly favored.

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

IR, UV, and NMR spectra

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.

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

The interaction of a substrate with an enzyme

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

The physical properties of substances

F o r e x a m p l e , t h e strength and melting point of a biomolecule ( e . g . f a t t y a c i d s ) depend on how well t h e m o l e c u l e s f i t together and on how s t r o n g t h e f o r c e s between them are.

generates IR spectrum

acetone

CO stretch CH stretch

acetaldehyde

generates UV-Vis spectrum

promotion of nonbonding electrons

1H-NMR

13C-NMR carbonyl C methyl C

methyl protons

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

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

E. Molecular Dynamics F. Langevin Dynamics G. Monte Carlo

Draw molecules in 2D

Construct DNA, RNA or protein from residues

Use/display molecules from

PDB files

Model Builder

Approximate 3D structures

Single point

MM QM

Geometry optimization

MM QM

Vibrational analysis

TS searching QM

Molecular and Langevin dynamics

Monte Carlo

Total energy of one

configuration

A stable configuration

IR spectra transition state conformation

Simulation of changing molecular

conformation with time and temperature, ensemble averaging

Methods:

Results:

QSAR QSPR

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 = ΣEstretch + ΣEbend + ΣEtorsion + ΣEnon-bonded

I. Computational Tools

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 free-energy surface with multiple global minima depicts folded, collapsed (compact) intermediate, and single-stranded structures

Tube Space-filling

Ball and Spoke Wire

•  MO methods seek an approximate solution to deceptively simple-looking differential (Schrödinger) equation ĤΨ = EΨ

Molecular Orbital Models

Ab Initio or Hartree-Fock Self-Consistent Field (HF-SCF) Methods

Results from solution to Roothaan-Hall equations which are simplified Schrodinger equations.

HΨ = EΨ

σ1s

σ2s

σ*1s

σ*2s

σ2p

π2p

σ*2p

π2p

σ1s

σ2s

σ*1s

σ*2s

σ2p π2p

σ*2p

π2p

σ1s

σ*1s

σ2s σ*2s

σ2p

π2p

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

-14.0

-12.0

-10.0

-8.0

-6.0

-4.0

-2.0

0.0

2.0

4.0

6.0

8.0

En

erg

y (

eV

)

Charge=(-1) Charge=(0) Charge=(+1)

-14.0

-12.0

-10.0

-8.0

-6.0

-4.0

-2.0

0.0

2.0

4.0

6.0

8.0

Energy

(eV)

Charge=(-1) Charge=(0) Charge=(+1)

DFT Study of Allicin major component of garlic

MO E-Level Diagram of Allicin

The energy of allicin decreases with upon oxidation – indicates antioxidant activity

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

1 eV = 3.674 x 10-2 hartree (au)

nS – π*S Allicin (0)

πC – π*S

nS – π*S Allicin (-1)

Theoretical UV-Vis Spectrum of Allicin

Calculated Electronic Properties of Allicin

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

(NIH Project: 023-2002)

The Cyclooxygenase Enzyme (Prostaglandin synthase)

Billones, J; Buenaobra, S. Phil J. Sci. 2010 (submitted for publication)

NR3

R4

R1 R2

N

R3

N

R1 R2

R3R3

R2R1

R2R1

R3

R2R1

NN

R3

R4

R2R1

R2R1 R1

ON

R2

R1

SR3

R2

Families of Tricyclic COX-2 Inhibitors

A (Pyrrole) 20

B (Imidazole) 114

C (Cyclopentene) 34

D (Benzene) 40

E (Pyrazole) 64

F (Spiroalkene) 28

G (Spiroheptadiene) 2

H (Isoxazole) 2

I (Thiophene) 1

-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)

Model 1 (3-D Parameters)

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.

Predicted Values versus Experimental Values for the Validation of Model 1

4.00

6.00

8.00

10.00

4.00 5.00 6.00 7.00 8.00 9.00 10.00

pIC50(exptl)

pIC

50(c

alc)

Validation of Model 1 (LOO Method)

q = 0.93 q2 = 0.87

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

C1

C8

C4

A B

C

sulfonyl

Representative Structure of COX-2 Inhibitor

Compound 294

Must be more positive

Must be enriched

Must be more negative

Must have e-releasing or moderately weak

e-withdrawing substituent

NH2, Br or CN

Activity of COX-2 Inhibitors

4

6

8

10

Inhibitors

pIC

50

A B C D EF G H I Prop

Celecoxib

Valdecoxib

Proposed Inhibitors

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

Design of Dengue NS3 Protease Peptide Inhibitors Panibe, J., Billones, J. 2008 BS Biochem Thesis, UP Manila

Electrostatic surface map of Panthotenate synthatase with bound curcumin analogue

Molecular Docking of Curcumin Analogues to Panthotenate Synthase

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

Hydrogen bonding and hydrophobic interactions of cucrcumin analogue with PS.

Green Chemistry

- also called sustainable chemistry "- design of products and processes that reduce or eliminate the 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. Design safer chemicals and products" Design chemical products to be fully effective, yet have little or no toxicity."

3. 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 modifications if possible. Derivatives use

additional reagents and generate waste."

7. Maximize atom economy" Design syntheses so that the final 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 efficiency"" 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."

Key Developments:"

1. Green solvent - CO2, water, solventless"

2. Green reactions"

- clean oxidation with H2O2"

- use of H2 in asymmetric synthesis"

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, fires, and releases to the environment."

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

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

Microwave, 30 s

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 “Metal-Ligand Complex”

Synthesis and Characterization of Biodegradable Polymers and Application in Drug Delivery System

Synthesis and Characterization of Poly-Vitamins and Mineral-Vitamins 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