Posts Tagged ‘research’

Modern drug discovery is characterized by the production of vast quantities of compounds and the need to examine these huge libraries in short periods of time. The need to store, manage and analyze these rapidly increasing resources has given rise to the field known as computer-aided drug design (CADD). CADD represents computational methods and resources that are used to facilitate the design and discovery of new therapeutic solutions. Digital repositories, containing detailed information on drugs and other useful compounds, are goldmines for the study of chemical reactions capabilities. Design libraries, with the potential to generate molecular variants in their entirety, allow the selection and sampling of chemical compounds with diverse characteristics. Fold recognition, for studying sequence-structure homology between protein sequences and structures, are helpful for inferring binding sites and molecular functions. Virtual screening, the in silico analog of high-throughput screening, offers great promise for systematic evaluation of huge chemical libraries to identify potential lead candidates that can be synthesized and tested.

A Brief History of CADD
1900: The receptor and lock-and-key concepts
P. Ehrich (1909) and E. Fisher(1894)

1970s: Quantitative structure-activity relationships (QSAR)
Limitations: 2-Dimensional, retrospective analysis

1980s: Beginning of CADD
Molecular Biology
X-ray crystallography, multi-dimensional NMR
Molecular modeling , computer graphics

1990s: Human genome
Combinatorial chemistry
High-throughput screening

The cost of drug discovery and development process has increased significantly during the past thirty-four years. The cost of drug development has increased from $4 million in 1962 to over $350 million in 1996 (Fig. 1).
Fig. 1: The cost of drug development from $4million in 1962 to over $350 million in 1996

Fig. 1: The cost of drug development from $4million in 1962 to over $350 million in 1996

Moreover, during this process, only a small amount of candidates will be examined in the clinic and few will be marketed. In 1950, it was estimated that 7,000 compounds had to be isolated or synthesized and then tested for therapeutic activity for each one that became a pharmaceutical product. The challenge is becoming more difficult: 10,000 compounds had to be evaluated in 1979, and this number could be as high as 20,000 today (Fig. 2).

Fig. 2: Timeline in a drug discovery project

Fig. 2: Timeline in a drug discovery project

The reasons for this are several-fold. The market for so called high value-added compounds is very competitive. The new compound must offer improved characteristics in order to be worthwhile for commercialization. Also there are serious hurdles regarding ease and cost of synthesis, patentability, safety, and social need for the new compound.

CADD Strategy Towards Drug Discovery
Computer-aided drug design (CADD) is one of these tools which can be used to increase the efficiency of the drug discovery process. CADD cannot maximize its utility in isolation and will not do so. Rather, it can form a valuable partnership with experiment by providing estimates when experiments are difficult, expensive, or impossible, and by coordinating the experimental data available. A close coupling between computational chemists and experimentalists allows information to flow immediately and directly between the two. This helps CADD chemists to better understand the details of the problem and to refine their approach.

CADD in Lead generation
In the early stage of a drug discovery process, researchers may be faced with little or no structure activity relationship (SAR) information. At this point, assay development and screening should be undertaken immediately by the high-throughput screening (HTS) group. The aim of these analyses is to select and test fewer compounds, whilst gaining as much information as possible about the dataset. However if a lead is known, then more focused approach can be adopted by searching for compounds with similar (two or three-dimensional) structures to the lead candidate or by substructure searching4. In substructure searching the query will retrieve those structures from the database that contain groups present in the primary lead. These molecules can then be screened in a biological assay.

CADD in Lead Optimization
In medicinal chemistry the lead optimization process concerns many aspects such as the optimization of the affinity for the biological target, the toxicity, the oral bioavailability, the cell permeability, the plasma binding, the ease of metabolism6. The principle employed is that any incremental change in the chemical structure produces incremental (positive or negative) changes in bio-activity and a systematic study of such cause and effect relationship is called structure activity relationship (SAR) study. The process is highly iterative and traditionally based on trial-anerror. When no structural data about the target is available, the lead optimization process can be made more methodological by using quantitative structure activity relationship (QSAR) studies. QSAR methods are used to attempt to correlate Two different approaches can be used in QSAR depending on the available compounds:

(1) Two-dimensional QSAR (2D-QSAR) and
(2) Three-dimensional QSAR (3D-QSAR).

This problem limits the applicability of CoMFA. In order to overcome this problem, some new approaches, which do not depend on a common alignment of the molecules, have been recently developed. Comparative molecular moment analysis CoMMA9, EVA or the WHIM are used because they provide three dimensional descriptors that are independent of the orientation of the molecules in space; they do not have to be aligned.

Software for Molecular Modeling

􀀼 General purpose molecular modeling (large & small molecules)
molecular mechanics, dynamics and multifunctional programs

􀀼 Quantum Chemistry calculations (small molecules)
molecular orbital or quantum mechanical calculations

􀀼 Database of molecular structures (large & small molecules)
software for storage and retrieval of molecular structure data

􀀼 Molecular graphics (large & small molecules)
programs to visualize molecules

􀀼 QSAR (small molecules)

Software for General Purpose Molecular Modeling

For workstations, minicomputers, and supercomputers (SGI, Sun, Cray, etc.)

AMBER — Peter Kollman and coworkers, UCSF Computer assisted model building, energy minimization, molecular dynamics, and free energy perturbation calculations.

Midas Plus — UCSF Computer Graphics Laboratory

CHARMM — Martin Karplus and cowrokers, Harvard

QUANTA/CHARMm — Molecular Simulations Inc. (MSI) molecular/drug design, QSAR, quantum chemistry, X-ray & NMR data analysis

Insight/DISCOVER — Biosym, Inc. Now MSI and Biosym became Accelrys Inc.

SYBYL — Tripos, Inc.

ECEPP — (Harold Scheraga and coworkers, Cornell)
MM3 — (Norman Allinger and coworkers, Georgia)

For personal computers (Apple, Compaq, IBM, etc.)

Alchemy III — Tripos, Inc. Structure building and manipulation,

Chem3D Pro — CambridgeSoft Corp.

Desktop Molecular Modeller — Oxford Elec. Publishing

Molecular Modeling Pro — WindowChem Software
Energy minimization, QSAR (surface area, volume, logP), etc.

PC MODEL — Serena Software

Molecular Modeling:

1. Data Analysis
Structural data (X-ray, NMR structure determination)
Biological data (bioinformatics)
Chemical data (QSAR of conventional compound synthesis and combinatorial chemistry)

2. Theory and Prediction
Molecular energy (structure and folding)
Molecular dynamics (conformational changes)
Molecular recognition (ligand and drug design)


Case Study #1
Virus type 1 Integrase (HIV-1 IN) inhibitors. HIV-1 IN is among one of the most important enzyme responsible for the HIV-1 replication cycle. Because of its essential nature in the replicative cycle of HIV-1, HIV-1 IN is an attractive target for the development of anti-AIDS drugs.
Starting from a pharmacophore hypothesis derived from a known inhibitor of HIV-1 IN, caffeic acid phenethyl ester (CAPE), a three-dimensional search of the NCI database was performed. From this search, 267 structures were found to match the pharmacophore, 60 of those were tested in an in vitro assay against HIV-1 IN and 19 were found to inhibit
both the 3’ processing and strand transfer.
The relevance of the proposed pharmacophore was then tested using a small three dimensional validation database of known HIV-1 IN inhibitors, which had no overlap with the group of compounds found in the initial search. This search strongly supports for the existence of the postulated pharmacophore and in addition, it hinted at the existence of a possible second pharmacophore relevant in the binding to IN.Using the second pharmacophore in a threedimensional search of the NCI database, 10 novel structurally diverse HIV-1 IN inhibitors were found.

Case Study #2
Recently a pioneering study was published by the group of Fesik. In this work, they elegantly combined the advantage of rational design and combinatorial chemistry by a new procedure called “SAR by NMR”. In the first step of this process, a library of low molecular weight compounds is screened to identify molecules that bind to the protein. Addition of a substrate with sufficient affinity to the 15N-enriched protein in solution yields a shift of the HSQC NMR signals for all groups near to the binding site.
In the next step, once a lead is identified, analogs are screened to optimize binding to this site. Searching for a second binding site is then undertaken in either the original screen or a screen conducted in the presence of the first fragment. The second ligand is then optimized. When the two optimized fragments have been selected, their location and orientation are determined experimentally by NMR or X-ray crystallography. Finally, on the basis of this structural information, suitable linkers for the two ligands are modeled on the computer.

The advantage of the Fesik approach is that one needs only weak binding for single ligands. Linking such weak binders provides not only the product of binding constants of the single substances but an additional entropic contribution which yields superactive compounds.

CADD approaches aim to increase the speed and efficiency in the drug discovery process which provides a somewhat more detailed map to the goal. The hope is that providing bit and pieces of information and by helping to coordinate the information, CADD will help to make the drug design process more rational. The many success stories of the use of CADD in the discovery of new drugs shows the utility of such analyses used in close coupling with traditional medicinal chemistry techniques.
CADD is now widely recognized as a viable alternative and complement to high-throughput screening. The search for new molecular entities has led to the construction of high quality datasets and design libraries that may be optimized for molecular diversity or similarity. On the other hand, advances in molecular docking algorithms, combined with improvements in computational infrastructure, are enabling rapid improvement in screening throughput. Propelled by increasingly powerful technology, distributed computing is gaining popularity for large-scale screening initiatives. Recent examples include the European Union funded WISDOM (World-wide In Silico Docking on Malaria) project which analyzed over 41 million malaria-relevant compounds in _1 month using 1700 computers from 15 countries, and the Chinese funded Drug Discovery Grid (DDGrid) for anti-SARS and anti-diabetes research with a calculation capacity of >1 Tflops per second. Combined with concerted efforts towards the design of more detailed physical models such as solubility and protein solvation, these advancements will, for the first time, allow the realization of the full potential of lead discovery by design.


The science of love is still in its infancy. Yet scientists are beginning to get early insights into the nature and origin of love. We can now look inside human brains to view changing patterns of activity and biochemical changes that take place during love, explore diverse human experiences of love, study how we select mates and woo lovers.

Addiction to love: In the brain, romantic love shows similarities to going mildly insane or suffering from obsessive compulsive disorder. Studies show that when you first fall in love, serotonin levels plummet and the brain’s reward centers are flooded with dopamine. This gives a high similar to an addictive drug, creating powerful links in our minds between pleasure and the object of our affection.
Lust is driven by sex hormones such as testosterone, which can go off-kilter too. As can levels of the stress hormone cortisol, and the amphetamine-like chemical phenylethlyamine, increasing excitement. Other hormones, oxytocin and vasopressin, Oxytocin is produced when couples have sex and touch, kiss and massage each other – the hormone makes us more trusting, helps overcome “social fear” and is important for bonding.

Select mates: Many factors add up to make us desirable to potential partners. There’s the obvious stuff like symmetrical features and good skin, which showcase a healthy development, immune system and good genes. Women look for tall men with masculine faces, kindness, wealth and status. Men prefer young fertile women with a low waist-to-hip ratio and who are not too tall. Neither sex is very keen on people who wear glasses.
Smell appears to be important as well; people are often more attracted to the smell of those who have different combinations of some immune system (MHC) genes to themselves. Mates with dissimilar MHC genes produce healthier offspring that are better able to thwart disease. People with similar MHC genes even prefer the same perfumes.

Love Relation Break: Falling in love may have evolved because people who focus their attention on a single ideal partner save time and energy, therefore improve their chances of survival and reproduction. Painful emotions develop when the reward centers of the brain, associated with the dopamine high of falling in love, fail to get their hit. Paradoxically when we get dumped we tend to love back even harder, as the brain networks and chemicals associated with love increase. Then love can turn to anger and hate, as the regions associated with reward are closely linked to rage in the brain. Finally when jilted lovers are resigned to their fate, they will often enter into prolonged periods of depression and despair.

Finally want to share something: “Even if you’re not a virgin, if you want to be a terrific lover, you have to have a solid foundation in sexual functioning. When you understand how the male and female anatomy works and how our bodies develop into sexual beings, you’ve mastered the basics______Dr. Ruth K Westheimer”

New Scientist:

Almost every Muslim is seriously concerned about what he or she eats. There is a complete code of dietary laws present in the Holy Quran for the followers of Islam. Some basic principles are described as all foods are permitted except those mentioned clearly in the Holy Quran. The most recent advancements of biotechnology in field of food industry like status of GMO’s, use of genes, enzymes, food additives or enhancer in food in Islam deduced by the Ijma or Qiyas. These if obtained from plant origin would be considered as Halal. If obtained from animals then Islamic Shari’ah put some restrictions about the animal that it should be permitted by Supreme law giver, and should be fit, clean and wholesome for health. The Muslim consumers should be particular and sensitive to the products they use for the Halal or haram issue. The recent advancements and impact of these advancements upon status of divine dietary law is very important. Reason for Muslims to observe these dietary laws are to follow the Divine Commandments.

“O mankind! Eat of that which is lawful and wholesome on earth…..” (Quran 2:168)

Principle for Halal food:
Halal means permissible and lawful while Haram means prohibited. It is exactly opposite of Halal. In general, every food is allowed for Muslims except what is prohibited either by the Holy Quran or by the Hadith. These rules of Shari’ah (Islamic law) bring freedom of choice for people to eat and drink anything they like as long as it is not haram (prohibited).

Alcohol and other intoxicants are also prohibited as:

“O ye who believe! Strong drink and games of chance, and idols and divining arrows are only an infamy of Satan’s handiwork. Leave it aside in order that ye may succeed” (Quran 5: 90)

Blood, pork, and the meat of dead animals or those immolated to other than God are strongly prohibited. It is also ordered that Halal animals should be slaughtered while uttering the name of Allah at the time of slaughter.
“Eat of that over which the name of Allah hath been mentioned, if ye are believers in His revelations” (Quran 6: 118)

“And eat not of that whereon Allah’s name hath not been mentioned, for lo! It is abomination. Lo! The devils do inspire their minions to dispute with you. But if ye obey them, ye will be in truth idolaters” (Quran 6: 121).

Genetic modifications (Use of gene):
The status of the process of genetic modification is controversial. According to some Muslim scholars and jurisprudence the process of altering some physical traits or nature created by Almighty is sin as it is mentioned in Quran clearly.

“….assuredly I will incite them and they will cut the ears of cattle; and assuredly I will incite them and they will alter Allah’s creation.” And he who takes Satan for a friend beside Allah has certainly suffered a manifest loss.” (Quran 4:119)

So according to this verse the alteration is not permitted as God is Supreme Power and Creator and no one can or would interfere with His power. Here two thoughts arise:
• Either alteration is just for alteration purposes (No purpose except beauty like in cosmetics or face surgery)
• Or alteration is for some useful purpose (For welfare of humankind) but it does not harm nature or other creatures.
Genetic modifications are permitted by some group of thoughts as these things are not mentioned clearly in the Holy Quran or Hadith (Traditions of Prophet Muhammad) because these are recent advancements. By the Qiyas and Ijma with some limitations it is allowed. Genetic modifications that especially are an issue of concern can be categorized as:

• From animals to plants and vice versa
• From insects to plants
• From animals to animals

Gene products (Enzymes):
Enzymes can be taken from animals, plants and microorganism also. They can be Halal or haram depending upon the source. If the source is Halal then they are considered as Halal as long as animal is slaughter according to Islamic Shari’ah, if not then enzyme will be mashbooh (doubtful). For example pepsin/proteases and catalyses are extracted from cattle/pig’s stomach and bovine liver respectively.

Halal is the dietary laws for Muslims. So the food industry needs to understand the requirements for producing products for Muslim markets. It also needs to understand the import requirements of countries with Muslim populations, which cover religious as well as safety aspects of imported food. The Halal foods should be mentioned clearly by labeling the hidden food ingredients. The Muslim scholars need to infer opinions with the advancement of biotechnology.

1. Khattak, J.Z.K., Asif M., Zubair, A., Hussain, M.W., Ghulam, A., Haider, K.K., Humaira, I., 2011. Concept of halal food &Biotechnology, Advanced Journal of Food Science and Technology, 3(5): 385-389.

2. Mathewson, P.R., 1998. Major biological sources of enzymes (Appendix C), in Enzymes, Eagan Press, St.Paul, MN, pp: 93-95.

3. Pickthall, M.M., 1994. Arabic text and English rendering of The Glorious Quran, Library of Islam, Kazi Publications, Chicago, IL.

AIDS (Acquired immune deficiency syndrome) is a disease caused by the virus known as HIV-1 (Human immunodeficiency Virus Type One). The HIV attacks the body’s immune system by destroying certain types of white blood cells (CD4+) called lymphocytes that help the body fight infection. A person with HIV infection may appear and feel healthy for many years. When someone is HIV-positive, that person has HIV antibodies in his or her body. Antibodies are proteins produced by the immune system to fight germs or infections Research suggests that the average incubation period from infection with HIV to the development of AIDS is approximately 10 years.

How do you get HIV?
HIV is transmitted through the bodily fluids of an individual carrying the virus. These bodily fluids are blood, semen, vaginal fluids, and breast milk. HIV can be transmitted in the following ways:

• Through the exchange or intake of blood, semen, or vaginal fluids while having vaginal, anal, or oral sex with someone who is HIV-positive.

• By sharing needles used to draw tattoos, give blood, or pierce ears or by sharing syringes used to inject illegal or prescribed drugs with someone who is HIV positive.

• Through perinatal transmission – when a HIV positive woman transmits the virus to her fetus during pregnancy to her baby while breast-feeding.

How HIV infects the body?
It is only now that scientists have learned how HIV infects the body. They have realized that it works in two phases, the M-tropic phase and the T-tropic phase, and that it looks for receptor sites to bond to. CCR5, a chemokine, is the second receptor site for HIV-1 in the M-tropic phase. Here is given the Process of HIV Replication (animation) in below:

HIV Replecation

HIV epidemiology in Bangladesh:
The first case of HIV/AIDS in Bangladesh was detected in 1989. Since then 1495 cases of HIV/AIDS have been reported (as of December 2008). However UNAIDS estimates that the number of people living with HIV in the country may be as high as 12,000, which is within the range of the low estimate by UNICEF’s State of the World’s Children Report 2009.
The number of AIDS patients has been on the rise in Bangladesh at a fast pace. Data from the country’s Health Ministry revealed that some 445 new HIV positive cases and 251 AIDS patients were detected in 2011. It showed 343 new HIV positives and 231 AIDS cases in 2010 while the number of new HIV positives was 250 and AIDS cases were 143 in 2009 & Some 37 people died of AIDS in 2010.
The overall prevalence of HIV in Bangladesh is less than 1%, however, high levels of HIV infection have been found among injecting drug users (7% in one part of the capital city, Dhaka). Due to the limited access to voluntary counseling and testing services, very few Bangladeshi’s are aware of their HIV status. Although still considered to be a low prevalence country, Bangladesh remains extremely vulnerable to an HIV epidemic, given its dire poverty, overpopulation, gender inequality and high levels of transactional sex. The emergence of a generalized HIV epidemic would be a disaster that poverty-stricken Bangladesh could ill-afford. It is estimated that without any intervention the prevalence in the general adult population could be as high as 2% in 2012 and 8% by 2025.

Medicinal plants as traditional medicine against HIV:
Traditional medicinal knowledge has been a means towards the discovery of many modern medicines. Traditional healers’ indigenous knowledge can help pinpoint medicinal plants used to manage HIV/AIDS. Bangladesh has a rich history of several traditional medicinal systems, among whom the most notable ones are the Ayurvedic, Unani, and the folk medicinal systems. Regarding HIV/AIDS related infections, many people think that using modern medicine is of no use, rather using traditional medicine or spiritual effects can help in this case.
The inclusion of anti-HIV ethnomedicines and other natural products in official HIV/AIDS policy is an extremely sensitive and contentious issue. many HIV-infected persons have access to antiretroviral drugs, but some still use ethnomedicinal plants and other natural products to treat opportunistic infections and offset side-effects from antiretroviral medication. Medicinal plants and other natural products including mushrooms are used as primary treatment for HIV-related problems such as skin disorders, nausea, depression, insomnia, and body weakness. Herbal medicines provide rational means for the treatment of many diseases that are obstinate and incurable in western systems of medicine. Phytomedicines are regaining patient acceptance because they have fewer side effects, are relatively less expensive, are easy to use and have a long history of use. Medicinal effects of plants tend to normalize physiological function and correct the underlying cause of the disorder. Sub-Saharan Africa has rich plant biodiversity and a long tradition of medicinal use of plants with over 3,000 species of plants used as medicines. Several of these plants may contain novel anti-HIV compounds. Indigenous knowledge of medicinal plant use also provides leads towards therapeutic concept thereby accelerating drug discovery; this is now being called reverse pharmacology. Thus, it is important to search for novel antiretroviral agents which can be added to or replace the current arsenal of drugs against HIV.
Some evidences with links:

a) A chemical from the Astragalus root, frequently used in Chinese herbal therapy, can prevent or slow progressive telomere shortening, which could make it a key weapon in the fight against HIV.
Chemical From Medicinal Plants May Be Used To Fight HIV

b) Genetically modified tobacco plants can grow specific proteins that scientists know will act on the HIV virus.
Fighting HIV in developing countries – with tobacco