The Class Of Integrase Inhibitors Biology Essay

Raltegravir belongs to the category of integrase inhibitors. It is the first integrase inhibitor to be registered.A The drug was approved by the U.S. Food and Drug disposal ( FDA ) in October 2007.

Integrase inhibitors work by barricading the integrase enzyme which catalyses the interpolation of the viral DNA into the host cell ‘s Deoxyribonucleic acid. This procedure stops the generation of viral familial information and hence no new viral cells are produced. This prevents other cells from being infected.Raltegravir was antecedently known as MK-0518.

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The trade name name for Raltegravir is isentress. This drug must be used with other retroviral drugs to handle HIV. The drug is besides used to handle HIV infections which are immune to multiple antiretrovirals such as non-nucleoside contrary RNA polymerase inhibitors ( NNRTI ) , nucleoside contrary RNA polymerase inhibitors ( NRTI ) and protease inhibitors ( Merck & A ; Co, 2010 ) .To understand the mechanism of the drug we need to first understand how the enzyme works. Human immunodeficiency viruses belong to retroviruses.

Retroviruss are those which have RNA as their familial stuff. The virus onslaughts CD4+ T cells one time inside the human organic structure, and injects the RNA and their cellular constituents into the host cell. The viral RNA is converted into viral DNA by a viral enzyme called contrary RNA polymerase.

The viral DNA so enters the karyon of the infected cell where it uses the host cell ‘s Deoxyribonucleic acid to copy the viral DNA.The following measure is the integrating. Integrase is the viral enzyme which catalyses the integrating of viral familial stuff into the septic cell ‘s DNA.

Integrase catalyses the 3 ‘ end point by taking dinucleotides from 3 ‘ terminals on both sides of viral DNA ( Savarino, 2007 ) . This leaves OH groups exposed on both termini resulting in the formation of a pre-integration composite, which so travels from the cytol to the karyon. The strand transportation measure takes topographic point in the karyon and the proviral DNA is formed upon the interpolation of the integrating composite into the host cell ‘s DNA. The spreads are so filled by cellular fix proteins.As raltegravir is an integrase inhibitor, it prevents the interpolation of the HIV DNA into the host cell ‘s Deoxyribonucleic acid by barricading the integrase enzyme. The HIV genome itself can non bring forth the new virus atoms. Thus the viral infection does non distribute out in the organic structure ( eMC, 2010 ) .

Structure, expression, functional groups

The chemical name for raltegravir is N- [ ( 4-Fluorophenyl ) methyl ] -1, 6-dihydro-5-hydroxy-1-methyl-2- [ 1-methyl-1- [ [ ( 5-methyl-1, 3, 4-oxadiazol-2-yl ) carbonyl ] amino ] ethyl ] -6-oxo-4-pyrimidinecarboxamide monopotassium salt ( Sathish et Al.

2008 ) . The empirical expression of the drug is C20H20FKN6O5, A and the molecular weight is 482.51 Daltons ( Sathish et Al. 2008 ) .The functional groups of the drug include a halogenated aromatic ring, aliphatic hydrocarbons ( methyl groups ) , imine groups, ether, and amide groups.Ionized hydroxylAmideImineHalogenated aromatic ringQuintessenceAliphatic hydrocarbons

Stereochemistry and conformation

Raltegravir is an achiral drug as it does non hold any chiral Centre. The drug therefore does non hold any enantiomorphs. There is besides no stereoisomer for the drug as there is no chiral Centre as the figure of stereoisomers is determined from the figure of chiral Centres.

If there is n figure of chrial Centres the figure of stereoisomers would be 2n.Staggered conformation would be favorable as there would be less steric hinderance between big groups. The altered conformation would be complementary to the mark where the drug acts upon. There are three rings in the construction taking up most of the infinite. The atoms arrange in such a manner that they are every bit far as possible from each other. The staggered conformation will hold the lowest energy and would be the most stable.

Eclipsed conformation is non stable as it has the highest energy. Isentress has 7 freely rotatable bonds. The bonds can revolve ensuing in 7 different conformations ( Scifinder Scholar, CAS ) .The drug has two hetrocycles – cyclic compunds which have one or more heteroatoms such as nitrogern, onygen and sulfur. The two heterocyclic compounds are the substituted oxadiazole ring and the substituted pyrimidine ring. Pyrimidine ring is besides found in the worlds ‘ familial stuff, DNA. The nucleic acids of human DNA consist of a deoxyribose, a phosphate group and a nitrogen-bearing base. The bases C and T contain substituted pyrimidine rings.

The uracil base of RNA besides has a substituted pyrimidine ring. The bases C and T are complementary to guanine and adenine as they can from hydrogen bonds with them. Similarly raltegravir besides can from hydrogen bonds with the enzyme integrase due to the presence of the substituted pyrimidine ring. Raltegravir can besides be referred as an alkaloid as there is more than N in the construction.Substituted pyrimidine ringSubstituted oxadiazole ring

Synthesis, preparations and packaging

Raltegravir is formulated as K salt. Its physical description is white to whitish pulverization. The drug is produced as tablets for unwritten disposal. The tablets are pink ellipse shaped ( Merck & A ; Co, 2010 ) .

The tablets have surfacing on them for effectual soaking up inside the organic structure. The extent of soaking up and release of the drug in the blood depends on its hydrophobicity and hydrophilicity. If the drug has a hydrophilic coating it will be absorbed more rapidly in the GIT and released quickly in the blood. The soaking up and release would decelerate down if the drug has a hydrophobic coating. The excipients in the coating are polyvinyl intoxicant, Ti dioxide, polythene ethanediol 3350, talc, ruddy Fe oxide and black Fe oxide ( eMC, 2010 ) .The film-coated tablets contain 434.4mg of raltegravir K as a spline which is tantamount to 400mg tablets. The inactive ingredients in raltegravir are microcrystalline cellulose, lactose monohydrate, Ca phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 ( contains 0.

01 % butylated hydroxytoluene as antioxidant ) , sodium stearyl fumarate, Mg stearate ( Sathish et Al. 2008 ) .The tablets are packed in High denseness polythene ( HDPE ) bottles with a child-resistant polypropene closing ( eMC, 2010 ) .

The packaging in plastic bottles indicates that the drug does non undergo free extremist oxidization as the chemicals undergoing free extremist oxidization have to be packaged in brown bottles or foil packaging.The drug is available in two battalions ; a bottle of 60 tablets and multiple-pack of 180 tablets consisting of 3 battalions of 60 tablets. There are non any particular storage conditions for the drug. It is stored at normal room temperature. The shelf life of the drug is 30 months.

The long shelf life and packaging in normal plastic bottles represents that raltegravir is a rather stable drug ( Rx list, 2010 ) .

Drug stableness: Potential sites of chemical instability and metamorphosis

The presence of ester groups makes a drug instable towards hydrolysis. Raltegravir does non hold any ester group so it can non undergo hydrolysis. Some chemicals can donate atoms to acquire stabilised by resonance. Raltegravir has more than one resonance signifier.

The more resonance forms a molecule has the stable the molecule is. The lone brace of negatrons on the O atom can travel in any way.The undermentioned resonance diagrams show a few possibilities of the transportation of negatrons and how different atoms stabilise by resonance.

The lone brace of the negatrons can travel to the C of the amide group on either side as the ruddy pointer shows in the diagram above.

Lipinskis regulation

Christopher A. Lipinski formulated the regulation of five in 1997 sing the bioavailability of orally active drugs. The regulation gives an indicant of a drug ‘s soaking up and pervasion in the biological systems but the pharmacological activity can non be predicted from the regulation ( Caltech library services ) .

Lipinski stated ( Lipinski, 1996 ) in his regulation that a compound should hold five or fewer H-bond givers, ten or fewer H-bond acceptors, molecular weight less than or equal to 500, and Log P value less than or equal to 5. Compounds that are classed as substrates for biological transporters are exclusions to the regulation.Raltegravir has 3 H-bond givers and 11 H-bond acceptors ( Scifinder Scholar, CAS ) . Nitrogen and O are the atoms which can accept and donate protons organizing H-bonds. The H bonds stabilise the compound and there would be strong interactions between the drug and its mark, integrase. Raltegravir obeys the lipinskis regulation up to some extent as it has less than 5 H-bond givers and merely one more H-bond acceptor than the regulation provinces.

Raltegravir follows the lipinskis regulation in the manner that its molecular weight is 482.51 Da which is less than 500. Log P is the log of divider coefficient. Earll ( Earll, 1999 ) defines the divider coefficient as “ the ratio of concentration of compound in aqueous stage to the concentration in an non-miscible dissolver, as the impersonal molecule ” .

The scope of Log P value given at Chemical Abstract Services ( Scifinder Scholar, CAS ) is from -1.7 to +0.3 ( -0.676A±1.000 ) . The log P value agrees with the lipinskis regulation as it is less than 5.

The divider coefficient can be calculated by taking antilog of log P. We get 0.21 by taking antilog of -0.

676. It means that merely 21 % of raltegravir will traverse the lipotropic phospholipid bilayer, and 79 % of the drug will remain in the blood plasma due to the presence of a figure of hydrophilic groups. Amines, amides, ether and the hydroxyl group are the polar and hydrophilic groups in raltegravir whereas the aliphatic and aromatic hydrocarbons are the non-polar hydrophobic fragments. The hydrophilic groups can organize strong H bonds. This is besides the ground that raltegravir is soluble in H2O and somewhat soluble in organic dissolvers like methyl alcohol and propyl alcohol ( Rx list, 2010 ) .

The pKa of the conjugate acid is 0.42 which means that raltegravir is a really weak base ( Scifinder Scholar, CAS ) . It will non readily accept protons because the lone brace of negatrons on both the N atoms of oxadiazole ring are non available as both the N atoms are sp2 hybridised.Raltegravir has a pKa value of 4.50 which shows that raltegravir is acidic. The drug stays in the acidic from as it is stabilised by resonance in this province. The pKa value can be used to find the ionization province at different pH values. The Henderson-Hasselbach given below can used to find the % of ionized drug at a certain pH.

% of ionization = 100 / [ 1 + antilog ( pKa – pH ) ]At pH 2, % of ionization = 100 / [ 1 + antilog ( 4.5 – 2 ) ] a‰? 0 %The drug will be in its acidic signifier at pH 2 of the stomachic fluid as the pH is lower than the pKa. The drug will be 100 % nonionized at pH 2 and it will easy be absorbed in the tummy as it can traverse the membrane. At pH 7 the drug will be about 100 % ionised so it will non traverse the phopholipid bilayer membrane and will be dissolved in the plasma. Similarly the drug will be 100 % ionised at pH 10 and will non traverse membranes.

The drug will hence be absorbed in the tummy at pH.The prescribed dose is 400mg to be taken twice daily, with or without nutrient. The maximal soaking up clip inside the organic structure is about 3 hours ( Rx list, 2010 ) . No accommodations are required in the dose signifier in patients with different age, gender, race, and cultural beginning.

The drug can non be prescribed to kids less than 16 old ages of age. The common side effects of the drug include sickness, concern and diarrhea ( BNF ) . The medical specialty should non be used during gestation as recommended by the maker. No research has been conducted in pregnant adult female but the drug is found to be toxic in animate beings ( BNF ) . The drug can cut down the viral burden to undetectable in the plasma and significantly increase the figure of CD4 cells ( Isentress patient booklet, 2010 ) .


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