Study of Substitution Vis -A -Vis Molecular Symmetry Effecting Transport Through Cell Membrane of Barbiturate Derivatives; Proposal for Compilation of E-Database as Computational Tool for Drug Activity.

 

Priyanka Jain*

Research Scholar, Department of Chemistry, BHOJ University, Bhopal (M.P.)

*Corresponding Author E-mail: pj2086@gmail.com

ABSTRACT:

Drug activity in biological system initiates from the entrance of the chemi particle through the cell membrane. This depends on the symmetry of the molecule, charge distribution due to the substituent and its related lipophilicity. Statistical relationship between mentioned parameter (QSPR approach²) may serve as bioinformatics method to predict and estimate the activity of a hypothetical molecular system. Several excellent models for the capture of macromolecular sequence and structure data are available. Current thinking asserts that the biological action of a compound is predictable if its chemical components understood. Such modules can be initiated at basic level with increasing trend of innovative e-teaching technologies using various multimedia and computational tools for collection of authentic dispersed database at one corner. The present attempt is a step in this direction. The simplest molecule in this direction selected for study is barbiturates and its derivates. Here the concentration dependence of drug activity has been examined using log P (hydrophobicity / lipophobicity) ahead of Hansch hypothesis and the ∏ electron density  of substituted molecule with drug activity .This study aims at variation in molecular dynamics , dipole moments, the molar volume and the Vanderwal interaction due to different substituent at 5a ,5b position of barbituric acid, methyl barbituric acid and their thio-barbiturates and their concomitant variation in the hydrophobic character or their motion through lipoidal membrane . If 3H –barbituric acid is being considered the substitution of allyl alkyl group show more favored lipophilicity thus rendering long active drug action but slower influence .To have a faster drug action 3-methyl substituted acid with allyl groups both in 5a and 5b position are expected to increase the drug action by at least 2-3 folds³. In case of allyl substitution the bulky gaps are more favorable to increase lipophilicity and thereby drug action. This type of data compilation along with the aid of new technology and tools of multimedia and computers i.e.  Bio-chemi-informatics will be helpful to predict and estimate the biological behavior of any hypothetical drug/biological molecule.

 

 

 

INTRODUCTION:

Advanced technologies addressing views of the complex biological systems in near molecular resolution are based on core technological innovation of analytical chemistry. However if there is a communal will, modern chemical informatics technology can provide what is required. Several excellent models for the capture of macromolecular sequence and structure data are available.

 

Current thinking asserts that the biological action of a compound is predictable if its chemical components understood. Such modules can be initiated at basic level with increasing trend of innovative e-teaching technologies using various multimedia and computational tools for collection of authentic dispersed database at one corner. The present attempt is a step in this direction.

 

It is an established fact that the lipophilicity a property, that states the solubility of molecule in lipid membrane. It is in fact responsible for penetration /migration of a chemi particle across the membrane. This membrane transport has a very significant role in biological processes. It regulates both endo and exo-osmosis responsible for intake of useful molecule and expulsion of unwanted chemi particle. The mandatory forces that a chemi particle should have to move across a membrane are (i) its composition (ii) spatial array and (iii) its dipolar effects leading to folding and opening of the specific chemi particle .The active site need to have an affinity for this chemi particle. The incoming moving particle must have optimal symmetry to move in the biological system and the spatial array to get fit at its site.

 

A massive database on molecular symmetry, their charge distribution due to different substituent, the concomitant hydrobhobicity imini lipofilicity and a statistical relationship between these mentioned parameter (QSPR approach¹) may serve as bioinformatics method to predict and estimate the activity of a hypothetical molecular system.

 

The present paper deals with the use of such substitution dependent symmetrical database for structurally related drug molecule of barbiturates. The structure – property relationship have been examined in light of the effect of substitution on hydrophilicity values.

 

MATERIAL AND METHODS

The principal mechanism of action of barbiturates is believed to be their affinity for the GABA_A receptor (Acts on GABA: BDZ receptor Cl^- channel complex), inhibitory neurotransmitter in the mammalian CNS. Barbiturates also block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. At higher concentration they inhibit the Ca²⁺-dependent release of neurotransmitters. Barbiturates produce their pharmacological effects by increasing the duration of chloride ion channel opening at the GABA_A receptor (pharmacodynamics: this increases the efficacy of GABA).

Structure of some barbiturates

 

Quantitative structure-activity relationships (QSAR) represent an attempt to correlate structural or property descriptors of compounds with activities. These physicochemical descriptors, which include parameters to account for hydrophobicity, topology, electronic properties, and steric effects, are determined empirically or, more recently, by computational methods². Activities used in QSAR include chemical measurements and biological assays. QSAR currently are being applied in many disciplines, with many pertaining to drug design and environmental risk assessment.

 

Here the concentration dependence of drug activity has been examined using log P (hydrophobicity/lipophobicity) ahead of Hansch hypothesis and the ∏ electron density  of substituted molecule with drug activity³ .This study aims at variation in molecular dynamics , dipole moments,the molar volume and the vanderwal interaction due to different substituent at 5a ,5b position of barbituric acid, methyl barbituric acid and their thio barbiturates and their concomitant variation in the hydrophobic character or their motion through lipoidal membrane.

 

The data in table 1 is already a study and  is used as secondary source of methodology.the table shows how the energy of molecular mechanics , vanderwaals force ,dipole moment , heat of formation , molecular volume ,area varies on changing the substituent in figure 1 above in molecule of barbiturates.

 

The goal of QSAR methodology is to develop several models to predict activity using correlation analysis employing statistical techniques.4,5 In this regard, mathematical multi-linear models, which have the advantage of formalizing the quantum superposition principle, are formed to correlate molecular structure with recorded activity,6-10 while being useful for predicting activity for new synthesized compounds from their computed structural information as well.

 

Our statistical models correlate anaesthetic activity of studied compounds with descriptors of  physical-chemical, electronic and geometrical nature. Among the physical-chemical descriptors we used the octanol/water partition coefficient, Log P, as a descriptor developed by the classic Hansch QSAR approach12 since it describes the molecular ability of a given compound (drug) to penetrate biological membranes. Information in ligand-receptor binding is supplied by descriptors from electronic class due to encoding electron distribution properties and, because the recognition of a molecule, by its biological receptor, is principally an electrostatic effect. Among the used electronic descriptors were polarizability, dipole moment or the energy of valence molecular orbitals (HOMO and LUMO).

 

RESULT AND DISCUSSION:

Hydrophobicity or lipobhobicity may be considered as the main driving force for any molecule to penetrate in biological system. Depending on data studied in table 1 and the structure correlation with symmetry we can also discuss classification of barbiturates. This can be stated here that 3-methyl substituted barbiturates are active drugs, associated with allyl substitution in 5a position .If 3H –barbituric acid is being considered the substitution of allyl alkyl group show more favored lipophilicity thus rendering long active drug action but slower influence.

 

TABLE 1.

Name of compound	Formula	R3	R5a	R5b	Emm	VDW	Dip. moment	H.F	mol. vol	Area
malonylurea pyrimidinetrione (barbiturates)	C₄H₄N₂O₃	H	H	H	119.64	14.58	1.816	31.37	131	118.467
5-allyl-5-(1-methylbutyl)barbituric acid	C₁₂H₁₃N₂O₃(Seconal)	H	C₃H₅	C₅H₁₁	1422.95	305.43	4.672	1245.81	312	244.06
5-(2-Bromoallyl)-5-(1methyl butyl) barbituric acid	C₁₁H₁₇N₂O₃Br(sigmodal)	H	C₃H₄Br	C₅H₁₁	1417.84	310.41	4.539	1248.11	336	265.51
5-Ethyl-5-(1-methyl butyl) barbituric acid	C₁₁H₁₈N₂O₃(NEMBUTAL)	H	C₂H₅	C₅H₁₁	1420.72	290.31	4.629	1219.06	301	231.859
5-methyl-5-phenyl barbituric acid	C₁₁H₁₀N₂O₃(RUTONAL)	H	CH₃	C₆H₅	438.98	90.37	1.871	325.84	256	24.9
5-furfuryl-5-isopropyl barbituric acid	C₁₁H₁₂N₂O₃(Darmavit)	H	C₄H₈O	CH (CH₃)₂	2670.26	566.52	2.166	2498.3	254	209.03
5,5-dipropyl barbituric acid	C₁₀H₁₆N₂O₃(proponal)	H	C₃H₇	C₃H₇	1353.45	233.81	4.241	11590.63	228	220.117
N-methyl-5-allyl-5-isopropyl barbituric acid	C₁₁H₁₆N₂O₃(Narconumal)	CH₃	C₃H₅	CH (CH₃)₂	1301.01	290.31	4.629	1219.06	285	219.732
N-methyl-5--(2-bromoallyl)-5isopropyl barbituric acid	C₁₁H₁₅N₂O₃Br	CH₃	C₃H₄bBr	CH (CH₃)₂	1113.06	248.45	3.066	951.04	317	252.03
N-Methyl-5 ethyl-5phenyl barbituric acid	C₁₃H₁₄N₂O₃(Mebaral)	CH₃	C₂H₅	C₆H₅	682.61	161.27	1.403	557.94	312	243.809
2-thiobarbituric acid	C₄H₄N₂O₂S	H	H	H	145.81	19.172	1.639	19.8	126	−
2-thio-5-ethyl - 5 (1-methyl butyl barbituric acid	C₁₁H₁₈N₂O₂S	H	C₂H₅	C₅H₁₁	293.598	293.6	2.746	1267.92	319	−
Emm :Energy of molecular mechanics(Kcal/mol) VDW : Vander wall forces H.F.: heat of formation (Kcal/mol) area : molar surface area

 

 

To have a faster drug action 3-methyl substituted acid with allyl groups both in 5a and 5b position are expected to increase the drug action by at least 2-3 folds³. In case of allyl substitution the bulky gaps are more favorable to increase lipophilicity and thereby drug action.

 

CONCLUSION:

PC model can also be used to study molecular dynamics and symmetry arrangement of substituted groups of barbiturates and also we can derive the quantitative statement on the structure–activity relationship of these drugs. This type of data compilation along with the aid of new technology and tools of multimedia and computers i.e bio-chemi-informatics will be helpful to predict and estimate the biological behavior of any hypothetical drug/biological molecule.

 

REFERENCES:

1.       Jerzy L. Mokrosz ,Structure-Reactivity Relationships in Barbiturates, Department of Organic Chemistry, Nicolas Copernicus Academy of Medicine, Dzierzyñskiego 14B st., 30048 Krakow, Poland.

2.       Hansch, C., Leo, A., and Hoekman, D. (1995) Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. American Chemical Society, Washington, D.C.

3.       Ghose AK, Crippen GM (1986). "Atomic Physicochemical Parameters for Three-Dimensional Structure- Directed Quantitative Structure-Activity Relationships I. Partition Coefficients as a Measure of   Hydrophobicity". Journal of Computational Chemistry 7 (4): 565–577.

 

 

Received on 01.09.2011        Modified on 04.09.2011

Accepted on 25.09.2011        © AJRC All right reserved