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RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November -2014 ISSN (e): Appli
Importance of Physicochemical Properties In Drug Discovery.
(Review Article)
Kapadia Akshay Bhupendra
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga (East), Mumbai. ABSTRACT:
Drug discovery is a complex and demanding physicochemical properties in drug discovery and enterprise. In recent years there has been a exploratory development. significant discussion discovery This review is based on how physicochemical developmental processes for new chemical properties of compounds can be optimized for entities, wherein various parameters like PK, drug discovery. toxicity, solubility, stability are addressed. The 'Rule of Five', gained wide acceptance as an approach to reduce attrition in drug discovery PROPERTIES:
and development. However, analysis of recent Most of the drugs used in medicine behave in trends reveals that the physical properties of solution as weak acids, weak bases, or sometimes molecules that are currently being synthesized in as both weak acids and weak bases. The term discovery companies "physicochemical properties" refers to the significantly from those of recently discovered influence of the organic functional groups within a compounds molecule on its acid-base properties, water development. The consequences of the marked solubility, partition coefficient, crystal structure, deviation in the physicochemical properties result stereochemistry, and so on. All these properties in a greater likelihood of lack of selectivity and influence the absorption, distribution, metabolism, attrition in drug development. Tackling the threat excretion, and toxicity of the molecule. The lead of compound-related toxicological attrition needs optimization stage of drug discovery usually calls to move to the mainstream of medicinal chemistry for specific methods that attempt to model decision-making. The impacts of these rules on properties such as oral absorption, blood–brain oral absorption are discussed, and approaches barrier penetration, distribution, metabolism and are suggested for the prediction, assessment and Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014



RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
its toxicity effects in the individual. Many ADME discovery projects represent major economic models include physicochemical properties as losses for the companies. Furthermore years and descriptors; calculation of these properties has to work on these discoveries and developments are be widely studied, because success or failure of lost. Ultimately, the introduction of a new drug the drug candidate solely depends on the candidate in the market is delayed. PK assessment should be seeded in the late discovery or the Christopher A. Lipinski has commented: predevelopment stage. This testing succeeds in ‘Drug-like is defined as those compounds that have sufficiently acceptable ADME properties and sufficiently acceptable toxicity properties to survive through the completion of human Phase I clinical trials [Lipinski, C. A. (2000)].' For a discovery project team it is important to focus on both activity and properties of the candidate [Kerns, E. H.et al. (2003)], if the focus is solely on the activity , the team may arrive with Figure 1. Representation showing optimisation of
a candidate whose properties are worse than the both Activity and Property. Figure2. Juggling HTS hit. Once a nanomolar activity is obtained it is hard to go back and fix the structural keeping poor candidates from progressing into modifications because the substructure may have development greatly reduces the rates of attrition. to be modified again which were added in order to Another useful anology is juggling. A proper enhance binding affinity. Optimization of drug- balance of crucial elements have to be maintained like properties like absorption, distribution, in order to achieve success. metabolism, excretion and toxicity (ADME/T) in Drug attrition is an alarming situation in recent time. A research carried out by J. Arrowsmith et selectivity) increases drug discovery success. al., (2013) shows that in 2011-2012, there were a The cost of development of new chemical entities total of 148 failures between Phase II and is generally high wherein failures of these Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014



RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
submission (also including Phase I/II studies in shows various parameters, causes and trends in patients and major new indications of already attrition rates. marketed drugs). Of these, 105 had reported reasons for failure. The majorities were due to a lack of efficacy (56%) or to safety issues (28%); here, failures that were due to an insufficient therapeutic index were included under the safety On comparing by phase bases, for the most recent year range, the proportion of failures due to lack of efficacy was higher in Phase II (59%), but still disturbingly high in Phase III and beyond (52%). The proportion of failures due to safety issues is higher in Phase III and beyond compared with Phase II at 35% and 22%, respectively, which may be due to safety issues that only become apparent in larger numbers of patients and/or When the failure rates are broken down by therapeutic area, oncology and central nervous system (CNS) disorders account for 44% (30% and 14%, respectively) of all the 105 failures between Phase II and submission for which reasons have been reported. However, almost 50% Figure 3. Trends in attrition rates. a. Of the 148
of CNS and endocrinology (diabetes) failures (13 failures between Phase II and submission in 2011 out of 29, and 4 out of 8, respectively) are and 2012, reasons were reported for 105; the excluded from these numbers because the reason majority of failures were due to lack of efficacy, for the failure has not been disclosed. Figure3 as shown on the left. On the right, the 105 Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014



RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
reported failures are broken down according to therapeutic area. b. Comparison of the reasons for failures in Phase II and Phase III trials in 2011 and 2012 with those in earlier periods that we reported BARRIERS IN DRUG EXPOSURE:
When a drug molecule is administered it has to: Dissolve in the biological fluids i.e. gastric fluids, intestinal fluids, blood plasma etc. Figure 4. Overview of Barriers in the pathway of
Survive a range of pH from 1.5 in the stomach to Drug Delivery to the target. 8.0 until it reaches the large intestine andfurther to Consequences of chirality on barriers and
Survive Intestinal and Gut bacteria. properties:
Permeate through the biological membranes in the Survive Metabolism by the enzymes. enantiomers, diastereo-isomers exhibit different Avoid active transport to bile. physicochemical properties, including melting Avoid excretion by kidneys. Reach the target organ. chromatographic behavior. The physicochemical Show its therapeutic activity and properties of a drug molecule are dependent not selectivity towards the target receptor. only on what functional groups are present in the Reduce partition and binding to unwanted sites. molecule but also on the spatial arrangement of these groups. This becomes an especially important factor when a molecule is subjected to an asymmetric environment, such as the human body. Proteins and other biological Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014


RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
macromolecules are asymmetric in nature, how a Metabolism (Binding, orientation of molecules particular drug molecule interacts with these positions to the reactive moiety) macromolecules is determined by the three- Plasma protein binding (Binding to specific target dimensional orientation of the organic functional groups present. If crucial functional groups are not Toxicity, such as CYP inhibition, hERG blocking occupying the proper spatial region surrounding Table 1. Effect of Sterioselectivity on Renal
interactions with the biological macromolecule (or Clearance
receptor) will not be possible, potentially Enantiomeric Ratio* therapeutic effect. However, if these functional groups are in the proper three-dimensional orientation, the drug can produce its interaction with the receptor. Therefore is very important for the medicinal chemist developing a new molecular entity for therapeutic use to understand *ratio of renal clearance of the two enantiomers. not only what functional groups are responsible for the drug's activity but also what three- dimensional orientation of these groups is needed. Log P: It is defined as the Log of the partition co- efficient of the compound between an organic phase and aqueous phase at a pH where all the pharmacodynamics properties of the molecule. compound molecules are in the neutral form Examples are as follows: [Rekker et al. (1992)]. Solubility (Crystal forms of enantiomers are The organic phase used is generally n-octanol and the aqueous phase is unionized water. Log P depends on the partition coefficient of the neutral Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014


RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
molecules between the two phases. Abraham et al. affinity to the polar aqueous phase than the non- have shown that Log P is affected by several polar organic phase. The fraction of molecules fundamental structural properties of the compound ionized depends on the pH of the aqueous [Mannhold et al (2009)]: solution, the pKa of the compound and whether Molecular volume: related to the molecular the compound is an acid or a base. For bases the weight of the compound which affects the size of neutral/cations ratio of the molecules in solution the cavity in the solvent to solubilize the increases with increasing pH, hence the Log D value increases with increasing pH. Conversely Di-polarity: affects the polar alignment of the for acids, the neutral/anion ratio decreases with compound with the solvent increasing pH, and Log D also decreases. Thus Hydrogen bond acidity: acceptance of hydrogen Log D is directly proportional to the neutral/ion bonds of the solvent. ratio of the molecules in the solution. Hydrogen bond basicity donation of hydrogen Parameters affecting Lipophilicity [Abraham et bonds to the solvent. Change in phases: Partitioning between octanol Log D: It is defined as the Log of the distribution
and water is different than that between co-efficient of the compound between an organic cyclohexane and water; this is due to the phase and aqueous phase at a specified pH (x) molecular properties of the phases. where the compound molecules are in the partly in pH: Affecting the degree of ionization the ionic form and a portion may be in the neutral Ionic strength of the solvent: Affects polarity, form [Hansh et al. (2004)]. molecular interactions and forms in-situ salts (as counter ions) with drug molecules. Co-solutes and co-solvents: May change the partitioning behavior of molecules even in smaller Log D depends on the partitioning co-efficient of the neutral portion of the molecule population plus the partioning portion of the ionized portion of the molecular population. Ions generally have greater Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
Lipophilicity co-relations [Hansh et al. (2004)]:
Effect of Log D on optimization
Permeability: Increase in lipophilicity increases parameters [Kerns, E. H.et al. (2010)]:
the permeability through the lipid bilayer hence increase in Absorption: Common impact on
Common impact
properties
Distribution: Increase lipophilicity, Increases Permeability low due Distribution low Plasma protein binding. to passive trans Oral absorption and cellular diffusion If MW less than 200, compounds occurs faster. permeation via Para- cellular diffusion Elimination: Compounds are protein bound, hence possible Metabolism low elimination and excretion of these compounds is Solubility moderate Oral absorption and Toxicity: Increased stay in the body may result into undesirable side effects. Oral bioavailability Permeability high [Lombardo et al. (2002)] also showed co-relations Metabolism moderate between the Volume of Distribution (Vd) and Permeability high lipophilicity. Increase in lipophilicity increases the (especially amines) plasma binding of the drug, increasing the Vd, thus leading to increase in the retention of the drug in the body. Table 2. Effect of Log P on optimization
pKa indicates the ionizability of the compound. It parameters [Kerns, E. H.et al. (2010)]:
is a function of the acidity or basicity of group(s) Property
the logarithmic measure of the acid dissociation constant (Ka). The logarithmic constant, pKa, is equal to −log10 Ka. Aqueous solubility pKa = - log ([H+]*[A-] / [HA]) Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
pH = pKa + log([B] / [HB+]) pKa = - log ([H+]*[B] / [HB+]) Thus, [HB+] / [B] = 10 (pKa – pH) Using these relationships, concentration of the neutral and ionic species can be calculated at any pH, if the pKa is known. When pH equals pKa, there is an equal concentration of ionic and neutral species in the solution. pKa is an important parameter because majority of the drugs contain ionizable groups. Most of the Figure 5. Concentration of neutral and ionic
drugs are basic, few are acidic and a minor part is species of acids and bases at pH above and below their pKa. As pKa determines the degree of ionization, it has To further simplify, acids with lower pKa value major effect on solubility and permeability. A are stronger because as the pH decreases there is a particular relationship between the permeability greater concentration of neutral acid molecules and solubility is defined which states that they are (HA) and a lower concentration of anionic acid inversely proportional. For Acidic molecules, molecules (A-) in the solution. Similarly bases decreases with increasing pH, with lower pKa values are weaker because as the because as acidity decreases, ionization increases pH decreases, there is a lower concentration of and diffusion of anionic moiety through the membrane becomes difficult, conversely the concentration of cationic base molecules (HB+) in increases as ionization increases. solution [Kerns E H. et al. (2001)]. Similarly for bases, as the pH decreases, 5.1. The Henderson-Hasselbalch equation [Avdeef ionization increases, permeability decreases and et al. (2001)] is a useful relationship for solubility increases. pKa also affects the activity discovery.For acids: of a structural series by showing changes in a + log ([A-] / [HA]) interaction at the active site of the target protein Thus, [HA/A-] = 10 (pKa – pH) [Martin et al. (1993)]. Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
SOLUBILITY:
class of compounds. E.g. Cimetidine, Nifidipine, It is defined as the maximum dissolved solute concentration under the given solution conditions. Class IV: Low Solubility and Low Permeability It determines the oral bioavailability and the (risk-philic): development of the compounds of intestinal absorption. Lipinski et al. stated that this class is costly and risky. No in-vitro/in-vivo solubility is a much larger criterion as compared to permeability in drug discovery [Lipinski et al. Hydrochlorothiazide, Furosemide, Tobramycin. (2012)]. The solubility classifications used in drug 5.2. Factors that affect solubility [Rouland M. discovery is given below [Waterbeemd H. (1998); Wu Chi-Yuan et al. (2005)]: Compound structure: More lipophilic, less the polar solubility and more hydrophilic, less the The Biopharmaceutics Classification System:
lipid solubility. In order to promote the optimum candidate to pKa: when the pH of the solution equals the pKa of development and streamline the transition to the compound its solubility is twice the intrinsic development, the BCS was invented. It divides all solubility of the compound. the drug candidates into 4 classes: Size: Larger the molecule, less its solubility. Class I: High Solubility and High Permeability Crystal lattice energy: Greater the energy, lesser (amphiphilic); the most ideal class for oral its aqueous solubility, due to stronger bonding of the crystal lattice. Class II: Low Solubility and High Permeability (lipophilic); formulation manipulations are used to Amorphous: Highly Soluble increase the solubility of these classes of Crystalline: Moderately Soluble Class III: High Solubility and Low Permeability Liquid: Polar liquids more soluble in aqueous (hydrophilic); prodrug strategies are used for these solutions than non-polar liquids. Composition and physical condition of solvents: Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
Type of solvents: Polarity solution. This has high implications for the Amount (%) of solvents solubility of compounds in various physiological Solution components fluids and solutions at different pH. Thus the pH: Acidic compounds more soluble in Basic pH solubility of a mono- acid or a mono-base is temperature: Increase in temperature increases B +H2O ↔ OH- + HB+ Medicinal chemists have the ability to alter the At equilibrium a mono-acid and a mono-base can solubility by manipulating the structure thus be described as: altering the physicochemical properties of the empirically derived a general solubility equation ‘S' is Solubility. for estimating the aqueous solubility of the A mathematical derivation of the Henderson- compound. The equation demonstrates the effect Hasselbalch equation provides the insight for of lipophilicity and crystal lattice energy on solubility as under: solubility [Yalkowsky et al. (1992)]. S = So (1 + 10(pH – pKa)) Equation: Log S = 0.8 – Log Pow – 0.01(MP – 25) S = So (1 + 10(pKa – pH))……………where ‘So' is Here, S is the Solubility, Log P the Intrinsic Solubility octanol/water partition co-efficient (measure of lipophilicity), and MP is the melting point exponentially with the difference pH and pKa. (measure of the crystal lattice strength). Examples are listed in the table. Barbital and Thus, solubility decreases 10 fold when Log P amobarbital have same pKa, but barbital have increases by 1 unit or the melting point increases much higher intrinsic solubility, because of its extra lipophilic chain in amobarbital, thus Therefore the solubility of a compound at a solubility of barbital is more as compared with particular pH is the sum of its intrinsic solubility amobarbital. Naproxen and i.e. the solubility of the neutral species as well as somewhat similar intrinsic solubility, but different the ionic species portion of the molecules in the pKa values; hence their solubility differs Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
extensively at pH 9. As the difference in pH and soluble in the later section of the small intestine pKa increases solubility increases exponentially because the region is more basic. [Lee Y. et al. (2003)]. Examples to prove the Table 5. Distribution of Drugs Based on the
above statement: Physiological pH in the Body.
Table 4. Solubility at a given pH is a given
Type of drugs
function of the intrinsic solubility of the
Neutral portion of the Molecules and solubility
Small intestine
5.5-7 Basic and Neutral of the ionized portion of Molecules [Lee Y. et
al. (2003)].
Neutral and Basic Intrinsic
Solubility @pH9
Muscle tissue
solubility
Adipose tissue
Lipophilic drugs Amobarbital 7.9
Barbital
5.3. Effects of solubility: As the compound dissolves, its concentration in the solution increases, hence its absorption occurs at a faster rate. Compounds with low solubility have low oral bioavailability. Cases of toxicity are also seen with compounds showing low solubility, due to retention of drug in the GI tract E.g. permeability and maximum absorbable dose. Cocaine, THC etc. The human GI tract shows a pH gradient along its solubility than low-permeability compounds to length varying from strongly acidic to basic. achieve maximum oral absorption [Bighley L.D. Acidic and basic drugs have different solubility throughout the GI tract. Bases are more soluble in the stomach and the upper part of the intestine due to ionization at acidic pH. Acidic drugs are more Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
Lipinski C A. (2000) has developed a useful graphical co-relation of solubility, permeability The velocity of the molecule passage through a biological membrane barrier is known as permeability [Goodwin J. T. et al. (2001)]. Prediction of in-vitro permeability can enhance a wide range of drug discovery investigations, help with understanding cell based bioassays, and assist prediction and interpretation of in-vivo Figure7. Graph for estimating solubility of
Discovery Compounds. encounter several different membrane barriers in In the above example, the compound has average the living system [Artursson P. (2002)]. They permeability (K include Gastrointestinal (GI) epithelial cells, a) and average potency ("1.0" mg/kg considering the dose to be fully absorbed), Blood capillary wall, Hepatocyte membrane, the compound should have minimum stability of Glomerulus, Restrictive organ barriers: Blood 52mcg/mL to be completely absorbed. In case of Brain Barriers and Target cell membrane. non-potent compounds, with a dose of about Permeation through the membranes occurs by five 10mg/kg and having average permeability, the major mechanisms: (a) Passive diffusion, (b) solubility must be 10 times higher i.e. Endocytosis, (c) Uptake transport, (d) Para- 520mcg/mL. These estimates help to provide cellular transport and (e) Efflux transport useful guidelines for optimization of solubility [Brahmankar D. M. (2005); Lin J. H. (1997)]. parameter during discovery. The following is the Lipid Bilayer Membrane Table 7. Classification of Drugs based on
Solubility [Kerns, E. H.et al. (2010)].
Less than 10mcg/mL Low Solubility
Moderate Solubility More than 60 mcg/mL Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
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Figure 8. Complex Model of a Lipid Bilayer
Another term that comes into play is the combined or composite permeability, which is the result of The phospholipid molecules assemble as a bilayer dynamic interaction of local conditions and how ranging approximately 490 nm in length, with the they affect the various permeability mechanisms. hydrophobic portion oriented inwards and the The conditions that may result in change of these hydrophilic phosphate heads towards the water molecules. Molecules diffuse through this bilayer gradient, transport affinity, molecular size and membrane by breaking the polar hydrogen bonds by shedding the hydrating water molecules and BLOOD-BRAIN BARRIER (BBB): diffuse inside, passing through the tightly packed BBB is restrictive for many compounds due region of the lipid chains around the glycerol owing to the p-glycoprotein efflux, absence of backbone and moves further to the more distorted Para-cellular permeation and limited pinocytosis. lipid region of the lipid aliphatic chains in the In order the drug to be administered to the CNS or middle of the membrane. Molecules with lower brain tissue its permeation through the BBB molecule weight passes through the membrane should occur. Many of the compounds generally more easily as compared to the higher molecular fail in achieving the desired therapeutic efficacy weight compounds, due to the tightly packed due to impermeability through the BBB. There are arrangement. Also, lipophilic molecules pass many mechanisms or say a combination of through the non-polar central core of the mechanisms that limit the permeability of these membrane more easily than the hydrophilic ones. drugs through the BBB. The BBB is associated Molecules then move through the other side with the micro capillary blood vessels that run chains and polar heads of the other side of the throughout the brain in close proximity to the membrane, thus regaining the polar hydrolysable brain cells. These cells provide the necessary water molecules and form hydrogen bonds again. nutrients and also take away the excreted products Membrane permeability differs from tissue to from the brain cells. They possess a surface area tissue, as composition of different tissues may of about 12mm2. The BBB consist of endothelial vary, like Gastro-Intestinal tract v/s the Blood cells that form a monolayer lining on the inner surface of the capillaries. The endothelial layer Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
RA Journal of Applied Research
Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
consists if mainly astrocyte and pericyte cells, Enhancements feature which generally increase which do not resist drug permeation but can, alter the uptake of nutrients like amino acids, peptides, endothelial cell characteristics. CNS drugs must glucose etc. and other endogenous compounds. permeate through the endothelial cells to penetrate Uptake enhancement is most commonly delivered the brain cells. The mechanism through which drugs permeate through the barrier is shown in the Nonspecific binding to plasma proteins and lipids in the brain tissue 8.1.Mechanisms that affect the BBB permeation Drug molecules that permeate the BBB are subject [Kerns E. H. et al. (2006)]: to no specific protein binding inside the brain. The Restricted physicochemical characters that limit free drug hypothesis states that binding of the passive diffusion drug to some other substrate reduces the Physicochemical properties considerations as therapeutic receptor concentration and thus reduce stated by Pardridge, as well as the compound in activity is seen. should have fewer hydrogen bond donors, higher Plasma Protein binding log P, lower PSA and a few rotatable bonds. PPB greatly limits the permeation to the brain, High efflux activity because the on/off kinetic models are low to PGp efflux limits the molecules before they can moderate and very little drug is available permeate reach the brain cell. Thus an efficient strategy is to reduce efflux by PGp Clearance of the compound from the ECF into the Lack of sites for Para-cellular permeation and capillary wall fenestrations The second interface between blood and the brain Tight junctions between the cells, is choroid plexus. The BBB interfaces with the Limited pinocytosis blood and the ECF of the brain. The choroid Endothelial cell metabolism and metabolic plexus interfaces with the blood and the CSF an is hence the blood cerebrospinal fluid barrier Increase in hepatic clearance affects the amount of drug reaching the brain Limitations of BCSFB is Uptake transport Surface area is 5000 time smaller than BBB Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
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Volume 1 Issue 1 Pages-18-43 November-2014 ISSN (e): Appl
There is little mixing of the components of CSF These rules were first used by Pfizer, prior to their publication and since then it has been widely used. CSF flows very fast from the brain tissue toward The rule states [Lipinski et al. (2004)]: the arachnoid villi Poor permeation and absorption are more likely CSF is turned over every 5 hours. > 5 hydrogen bond donors (expressed as the sum Figure9. Acids Poorly Permeate BBB, whereas of all OH and NH) Bases have good BBB Permeability [Clark D. E. Molecular weight > 500 >10 hydrogen bond acceptors (expressed as a sum predominantly negatively charged phospholipids head groups in the BBB [Liu X. (2006)]. About 75 Substrates for biological transporters are % of the prescribed drugs are basic, 19% are exception to the rule. neutral and 6% are acidic. A study conducted by Veber on rats showed, molecular flexibility, polar surface area and hydrogen bond count are important determinants for oral bioavailability. Rotatable bond also account in the picture, which may be calculated electronically or manually. Calculation of PSA can be done using sophisticated softwares. PROPERTY
PROFILING
Veber rules for good bioavailability in rats [Veber FROM STRUCTURE:
D. et al. (2002)]: Lipinski rules:
≤ 10 rotatable bonds The declaration of ‘The Rule of 5' as stated in the report of Lipinski et al, opened a new way for the ≤ 12 total H bond donors and acceptors classification of the physicochemical properties of the drug compounds [Lipinski et al. (2012)]. Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
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bond donors >2. This is in agreement that hydrogen bond donors are limiting than hydrogen Another set of rules compiled by Clark [Clark D E. (2003)] and Lobell [Lobell et al. (2003)] suggests that the structure should have the Figure 10. Application of Lipinski and Veber rule
Buspirone. Refer Table 8. PSA < 600 – 700 nm2 Table 8. Calculations for Buspirone
Lipinski Rules
Veber Rules
Opera el al proposed set of rule of 3 for lead-like Rotatable Bonds = 5 The ‘Rule of 3' for lead-like compounds as Total Hydrogen Bonds = 31 proposed by Oprea [Opera et al. (2002)]: Molecular weight ≤ 300 Good Absorption
Good Oral Bioavailability Rotatable bonds ≤ 3 Pardridge- rules for BBB permeability:
Hydrogen bond donors ≤ 3 Physicochemical properties greatly affect BBB Hydrogen bond acceptors ≤ 3 permeation. A set of physicochemical rules was Polar surface area (PSA) ≤ 600nm2 first proposed by Pardridge [Pardridge (1995)]. Rules of Thumb for a Given Set Molecular The structure of the compound should have: Hydrogen bonds (total): < 8 -10 A set of simple, consistent structure–property Molecular Weight < 400-500 guides have been determined from an analysis of a No acidic moiety. number of key ADMET assays run within GSK: Sparklin [Maurer T S. et al. (2005)] further solubility, permeability, bioavailability, volume of suggested that Hydrogen bond acceptors <6 and distribution, plasma protein binding, CNS Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
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penetration, brain tissue binding, P-gp efflux, one or more of the parameter lie above the cut- 1A2/2C9/2C19/2D6/3A4 Figure 11. Indication of How Changes in Key
models have been developed on almost all the key Molecular Properties will affect a Range of ADMET Parameters. a) For Neutral Molecules, b) pharmaceuticals industry and are reviewed in For Basic Molecules, c) for Acidic Molecules, d) detail in many researches. Much of the research For Amphiphilic Molecules. a Expressed relative on in-silico ADMET and QSPR (Quantitative to the mean value of the data sets. MWT and Structure Property Relationship) models is based ClogP cut-offs of 400 and 4, respectively, are on more advanced statistical data as reported in used. * Optimum ClogP bin is 3–5 with respect to the literature. To counter the general reduction in permeability. ** Average to high volumes rather interpretability of QSPR models, an attempt was than high, low, or average generally considered made to demonstrate a set of simple rules of optimum. *** Low CNS considered optimum, thumb based on large data sets a range of ADMET although for targets in the brain, this will be assays run within GSK [Gleeson M. P. (2008)]. reversed. **** Some isoforms show a nonlinear The results were compiled and a set of rules were relationship with ClogP and/or MWT. These are formulated wherein qualitatively predict the ADMET issues most likely to be experienced for a molecule based on its ClogP, MWT, and ionization state, without the need for complex computer simulations. The likelihood of a molecule having a particular It is clear that almost all ADMET parameters increase with either increasing MWT and/or ClogP, a single combined ClogP/MWT category has been used for simplicity. Molecules lie in the more desirable category if both MWT < 400 and ClogP < 4, while they are classified as less-desirable should Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
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Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
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The rather simplistic modeling used here has the advantage of allowing scientists to make cross comparisons between a large numbers of ADMET assays. It then becomes easy to assess in a qualitative fashion how changes in the key physicochemical parameters will impact each of the different ADMET parameters in a particular This simplicity can be useful in a lead optimization environment where one does not optimize ADMET parameters in isolation. Such simple rules could also be used in the Hit-to-Lead stage to identify the likely ADMET issues of a given lead, allowing resources to be more effectively directed to the areas identified before the molecule enters lead optimization. These rules aid in the assessment of compounds. They are typically used for the following Anticipating of the drug like properties of potential compounds i.e. lead molecules when planning synthesis. Evaluating the drug-like properties of compounds being considered for purchase from a compound Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
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CONCLUSION:
REFERENCES:
Over the years, strategies for reducing failure of Book References:
lead molecules have been stated and optimization 1. Beale, John M., and John Block. Organic of physicochemical properties has been an medicinal and pharmaceutical chemistry. important parameter. Figure 44 shows how Lippincott Williams & Wilkins, 2010. incorporation of evaluation and optimization of 2. Brahmankar, D. M., and Sunil B. physicochemical properties into drug discovery Jaiswal. Biopharmaceutics from target hits to final drug molecule can be pharmacokinetics: A treatise. Vallabh fruitful. During lead optimization and parameters prakashan, 2005. such as Absorption, Distribution, Metabolism, 3. Foye, William O. Foye's principles of Excretion and Toxicity (ADME/Tox) properties medicinal chemistry. Eds. Thomas L. should be emphasized throughout the entire Lemke, and David A. Williams. Lippincott discovery process. This approach also helps to Williams & Wilkins, 2008. improve efficiency, as problematic compounds are 4. Kerns, Edward, and Li Di. Drug-like removed and delay or failures of candidates are properties: concepts, structure design and optimization. Academic Press, 2010. Article References:
"Determination of solute lipophilicity, as log< i> P</i>(octanol) and log< i> P</i>(alkane) divinylbenzene) and immobilised artificial membrane stationary phases in reversed- high-performance Figure 12. Flowchart for Optimized Drug
chromatography." Journal Chromatography A 766.1 (1997): 35-47. Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
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26. Kerns, Edward H. "High throughput pharmacological toxicological methods, 44(1), 235-249. discovery." Journal pharmaceutical sciences 90.11 (2001): 1838-1858. properties and the causes of poor solubility 27. Lee, Yung-Chi, Philip D. Zocharski, and permeability." Brian Samas. "An intravenous formulation pharmacological toxicological decision tree for discovery compound methods44.1 (2000): 235-249. 33. Lipinski, Christopher A. "Lead-and drug- journal of pharmaceutics 253.1 (2003): revolution." Discovery 28. Li, Ying, et al. "Artemisinin derivatives: Technologies 1.4 (2004): 337-341. activity." Bioorganic & medicinal chemistry "Experimental 11.20 (2003): 4363-4368. approaches to estimate solubility and 29. Lin, Jiunn H., and Anthony YH Lu. "Role of pharmacokinetics and metabolism in settings." Advanced delivery reviews 64 (2012): 4-17. development." Pharmacological 35. Lipper, ROBERT A. "How can we reviews 49.4 (1997): 403-449. optimize selection of drug development 30. Lin, Jiunn H., and Anthony YH Lu. "Role candidates from many of pharmacokinetics and metabolism in 36. Liu, Xingrong, et al. "Unbound drug concentration in brain homogenate and development." Pharmacological cerebral spinal fluid at steady state as a reviews 49.4 (1997): 403-449. surrogate for unbound concentration in 31. Lipinski, C. A. (2000). Drug-like brain interstitial fluid." Drug Metabolism properties and the causes of poor solubility and Disposition 37.4 (2006): 787-793. and poor permeability. Journal of 37. Lobell, Mario, László Molnár, and György M. Keserü. "Recent advances in the Kapadia Akshay Bhupendra RAJAR Volume 1 Issue 1 November 2014
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Ethio. J. Appl. Sci. Technol. Vol(4):65-75(2013) 65 ORIGINAL ARTICLE In vitro Nematicidal (Anthelmintic) Property of the Seed Extracts of Anamirta cocculus (Linn.) Against Pheretima posthuma (L. Vaill.) Umer Qadir and Paul, V.I.* Department of Zoology, Annamalai University, Annamalainagar 608 002, Tamil Nadu,