Major interest:

• Computer simulations of biological active molecules (such as lipid) and their interactions with pharmaceutically important molecules.
• Application of IT and modelling tools in pharmaceutically relevant problems

Interactions of penetration enhancer on lipid membrane.
Habibah A Wahab¹, Jamshed Anwar², David Barlow², Kenneth Merz, Jr.³, K. V. Damodaran^3
1School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia. ²Department of Pharmacy, 
King's Colloge London. ³Department of Chemistry, Pennsylvania State University.

The success of transdermal drug delivery to date is still limited to only a few drugs because the skin itself represents the greatest barrier to percutaneous permeation. One way to reduce this barrier is by incorporation of a penetration enhancer such as Azone in the transdermal delivery device. Azone is thought to exert its effects by interacting with the stratum corneum lipid lamellae and causing an increase in ‘fluidity’. The increased disorder is thought to facilitate the diffusion of molecules through the hydrocarbon region of the bilayer. MD simulations of a DPPC bilayer, DPPC bilayers containing two and four molecules of Azone were carried out. Azone incorporation into the lipid bilayer results in increased disorder of the bilayer as well as increased DPPC and water diffusion. Based on these results a model was proposed to illustrate the mechanism for drug-penetration enhancement through a lipid membrane in the presence of Azone. This model proposes that Azone perturbs all of the diffusion zones within the lipid bilayer and reduces the permeability resistance in these regions, thus explaining Azone ability in enhancing both lipophilic and hydrophilic drug molecules.

Automated Docking and Molecular Dynamics simulations
 of Isoniazid on Mycobacterium Enzymes.
Khawaja Sohail Qamar, Habibah A Wahab, Pazilah Ibrahim, Amirin Sadikun, Choong Yew Siew.
School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia. 

In our studies we have attempted to explore the mechanism of action as well as resistance of isoniazid with the help of various Molecular modelling techniques. We have docked isonicotinic-acyl-NADH into the wild-type and mutant-type InhA; an enzyme involved in the biosynthesis of mycolic acids in Mycobacterium tuberculosis. All models of ligand and enzymes were generated with the help of Amber6 program package which are then docked into the wild-type and mutant-type InhA active sites individually using computational automated docking package AutoDock 3.0, wherein a new hybrid Lamarkian genetic algorithm is implemented in complex with Pseudo-solis and Wets local search. Isonicotinic-acyl-NADH bounds with wild-type InhA in almost the same conformation as found by x-ray crystallography. The residue Phenylalanine 40 of the wild-type InhA was found to make specific interactions with the adenine rings of isonicotinic-acyl-NADH that might help to position the complex of activated form of isoniazid and NADH but in case of mutant-type InhA, the adenine ring drifts away as a result of strong interactions of the mutant residue Alanine 94 with the phosphates in the middle of isonicotinic-acyl-NADH. The predictions of these interactions at the molecular level can be of primary importance in elucidating the resistance developed in the newly emerged mutant strains of Mycobacterium tuberculosis.

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Investigation of  the Binding Properties of Some Flavonoids to Calcium
  using Molecular Modelling Techniques.
Nornisah Mohamed, Habibah A Wahab, Zhari Ismail, Norhayati Ismail, Ng Pei Ling
¹School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia. 

Urinary stones is one of the oldest diseases known to man. It is estimated that as many as 15% of the population will developed urinary stone. The stone can caused extreme pain, urinary tract infection and obstructive uropathy which can lead to morbidity. Howeververy few individual dies due to this disease.

There are a few types of stones that can developed such as calcium oxalate, uric acid, calcium phosphate, struvite and cystine. The most common stone is made of calcium oxalate. Calcium being the main constituent of bone and is always present in blood and urine. Oxalate on the other hand is a by-product of metabolism which is also present in many of our foods. When calcium and oxalate combine, they form a very insoluble salt that easily forms a solid stone which can never be dissolved.

The effects of flavonoids on the growth of calcium oxalate crystals have been shown. These compounds have an inhibitory activity on the crystal growth. The flavonoids inhibit in both normal urine and stone forming urine. The flavonoid will form a complex with calcium ion and the stability of the complex depends on the position of the complex and the substitution groups of the flavonoids. From this study, flavonoids have seen to be useful for the prevention of calcium oxalate stone formation and can be used clinically as the alternative way for the urinary stone disease.  

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Computer Aided Drug Design of Anticancer Drug: 
The Cancerogenesis Of Aromatic Compounds
Habibah A Wahab, ² Janez Mavri, ¹ Nornisah Mohamed, ³ Noorsaadah Abdul Rahman
¹School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia. 
²National Institute of Chemistry, Ljublyana, Slovenia. ³Department of Chemistry,  
Universiti Malaya, Kuala Lumpur, Malaysia.

Cancers are among the leading causes of death in developed countries as well as in Malaysia. It is believed that 80 percent of all carcinoma (including cancer of the cervix) originate from the environment. Tobacco smoke, radiation, various chemicals are the most common effects of the environment. Common to all these influences of the environment is damage of the nucleic acids. It was observed already many years ago that aromatic compounds are often associated with the development of carcinoma. The chemical pathway leading to the damage of DNA by aromatic compounds is as follow: under the influence of cytochrome P450 the aromatic compounds are epoxidized. This step is followed by alkylation of guanine by epoxi compound. Alkylated DNA is not able to replicate properly and such a damage is believed to be the the main cause of the cancerogenesis.The epoxidation is believed to be the fast step, while the electrophylic attack is believed to be the rate limiting and therefore essential step. We will study the alkylation step. Using ab initio MO and DFT calculations we will calculate the activation energies for the alkylation reaction. We will make a comparison with the experimental data concerning the cancerogenicity of various aromatic compounds (benzene, benzpyrene,aflatoxin). Moreover, we plan to follow the alkylation reaction using high-resolution NMR on model systems, that is available in Ljubljana as well as in Malaysia. We will address the question of irreversible inhibition of various proteases and therewith associated issue of specificity. The study will provide deeper insight into the molecular biology of cancer and hopefully give some new strategies for chemotherapy of cancer.