Molecular modelling of the antiarrhythmic-receptor interaction

Journal of Molecular Structure (Theochem), 307 (1994) 35-46 0166-1280/94/$07.00 0 1994 - Elsevier Science B.V. All rights reserved

35

Molecular modelling of the antiarrhythmic-receptor interaction Milan Remko*pa, Steve Scheinerb, Bernd Michael Rode” aDepartment of Chemical Theory of Drugs, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovak Republic bDepartment of Chemistry, Southern Illinois University, Carbondale, IL 62901, USA “Theoretical Chemistry Division, Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 52a, 6020 Innsbruck, Austria

(Received 28 June 1993; accepted 27 July 1993) Abstract Theoretical methods are used to study the antiarrhythmics lidocaine, tocainide and mexiletine. The proton affinities of those drugs were computed by means of the AM1 method. The superposition of the stable conformations of these drugs was studied using the MOLGEN 1.0program. Ab initio SCF methods were applied for the study of the interaction of their polar groups with the presumed receptor sites in the cardiac membrane. On the basis of these calculations, a two-centre binding model for the antiarrhythmics to their receptor is proposed. The possible proton transfer from the drug towards the receptor was also studied, including the influence of small cations and water.

Introduction

Antiarrhythmics are drugs which are used in the clinical practice for the therapy of the diseases of the cardiovascular system. The structural heterogeneity of these drugs allows their pharmacological classification according to electrophysiological parameters into several subgroups [l]. The molecular mechanism of action of antiarrhythmics is not yet thoroughly understood. Lidocaine, tocainide and mexiletine are antiarrhythmic agents which belong in the class Ib category [ 1,2]. The chemical features that are essential for the activity of those local anaesthetic-like antiarrhythmics can be depicted as:

Ar-X-(CHa,-N+-H

/RI ‘R

* Corresponding

I

author.

SSDI 0166-1280(93)03570-W

Ar represents the lipophilic aromatic group which is separated by an intermediate alkyl chain (containing polar group X capable of hydrogen bond formation) from the hydrophilic amine part. Their main antiarrhythmic effect is based on the interaction of these drugs with the sodium channel of the cardiac cell [2-41. However, the nature of these nonspecific interactions with myocardial membranes is not well defined. Theories of the antiarrhythmic-sodium channel interaction based on the currently accepted models (modulated receptor hypothesis [5] and guarded receptor model [6,7]) agree that a channel is blocked completely when a drug is bound and that it only conducts when unbound. In order to gain more information about the nature of antiarrhythmic-membrane interactions on the molecular level we have applied the means of theoretical chemistry. In this work, as in several earlier work [8,9], ab initio SCF calculations

36

M. Remko et al./J. Mol. Struct. (Theochem) 307 (1994) 35-46

antiarrhythmic-model membrane modelling polar group interactions were carried out. In the present paper, we report the results of a deeper theoretical study of the antiarrhythmics lidocaine, tocainide and mexiletine. Further, we investigate the intermolecular hydrogen bonds formed between polar groups of the drugs and the polar carboxylate, phosphate and amide groups of the lipoprotein and phospholipid domains of membranes. Finally, the effects of water and small cations (H +, Li+, Na+) on the energetics of proton transfer and hydrogen bonding between an ionized amine and the carboxylate anion were also studied.

correlation. However, because we are primarily interested in studying general trends, extension of the basis set and inclusion of correlation would not be expected to alter any of our qualitative conclusions [ 161. The intermolecular parameters R, I and (Yof the complexes given in Fig. 1 were energy-optimized, holding fixed the internal geometries of each subunit in the ab initio optimized monomer structures. In all cases the bridging proton was moved along the hydrogen bond axis. The interaction energy AE,n was determined as the difference between the total energy of the isolated molecules and that of the model complex (EAT)

Computational

AEHB=

details

The geometry of lidocaine (2-diethylaminoacettocainide (2-amino-2’,6’2’,6’-dimethylanilide), propionoxilidine) and mexiletine (I-(2,6-dimethylphenoxy)-2-aminopropane) were fully energyoptimized using semiempirical MO-SCF method AM1 [lo]. The molecular modelling studies of the above mentioned drugs were carried out by means of the MOLGEN 1.0program [l 11. The AM1 method allows the calculation of the standard enthalpies of formation [12] AHT,zgs. The proton affinity of base PA(B) can be computed by Eq. (1)

(EA+EB)

-EAB

The H-bond energies of ion-coordinated (Fig. 1) are AEHBN

= (4~

+EB)

- E(IA...B)

(2)

complexes

(3)

where EIA is the total energy of the optimized anion-cation system (Hf, Lif, Na+). The superposition error, typical for basis sets of the minimal type, was estimated and corrected by the Boys-Bernardi counterpoise correction [171. The AM1 calculations were carried out using the AMPAC program [18], and ab initio computations using the GAUSSIAN so [19] and GAUSSIAN 90 [20] programs.

PA(B) = AH:, r(H+(g)) + AH:, r(B(g)) - AH;. r(BH+ (g))

(1)

AH:,, represents the heat of formation of the For stated between parentheses. species AHT,,ss(H+(g)) the experimental value of 1537.1 kJmol_’ is taken [13]. Ab initio molecular orbital methods were used for the calculations of the interaction energies, equilibrium geometries, and proton transfer of the hydrogen bonded complexes investigated (Fig. 1). In these computations, the MINI-l [14] and split-valence 3-21G [15] basis sets were applied. The quantitative reproduction of all the features of the system investigated would require a larger basis set and inclusion of electron

Results and discussion Physico-chemical properties of drugs under study

The binding and unbinding of antiarrhythmic agents to the specific receptor within the sodium channel can be influenced by several molecular factors (molecular conformation, molecular size, lipophilicity, pH) [2]. In order to determine some of these physico-chemical parameters of lidocaine, tocainide and mexiletine, we have studied in our publications conformational previous the properties of these drugs [21-231. Because the antiarrhythmics investigated are weak bases, both charged and uncharged forms coexist at the pH

M. Remko et al,/J. Mol. Struct.

(Theochem)

307 (1994) 35-46

YazH .-A. H,C

---j-

0-'C

c\

-7

Hat-h

9

'H

a

hi-H

.

H

..G=c/

1-I

HH

-H

R

H’

CHa

6

1 0

Had-l

\

I-

Had

I

A,0-P

,,lr;-H...

\ .\

R

OH

a

'OH

CLa

7

2

‘/CHa =?_ . \c

0

I&

Hy

‘\‘l;-H... AoLC

I

-)

/

CH a -

H\N

‘H

I?

CHa

a

/

-

HIN,-.H ‘H

R

\ CHa

3

8 0

HI!

+

-“lrt__H...

A,, 0-p

I \;‘

OH

OH

4

HO.-

; OH

9 (10)

5

Fig. 1, Molecular structure of complexes studied, indicating definition of intermolecular

parameters

R, r and CL

38

M. Remko et al/J. Mol. Struct. (Theochem)

of the physiological medium. The conformational investigations [21-231 of those species for lidocaine, tocainide and mexiletine, showed that considerable differences exist between the conformational flexibility of the bases, their cations and their salts. The unprotonated bases exhibit a fairly high steric flexibility. For the salt only one conformer is stable. In the case of the cations the most stable conformers were found with an intramolecular N+-H . . .O hydrogen bond. However, in the clinically used hydrochlorides, lidocaine [24] and mexiletine [25] possess a different conformation in which both oxygen and amine nitrogen atoms are oriented in such a way that it eliminates their mutual intramolecular interaction. In order to model a situation that may occur in a biologically active environment we examined lidocaine and mexiletine as the conformations found in their salts [24,25]. The rigid superimposition of the crystal structures of the lidocaine and mexiletine hydrochlorides using the program MOLGEN 1.0 is presented in Fig. 2. The fitting was carried out with respect to the carbon atoms 1, 2 and 6. A goodness of fit was expressed in terms of root mean square value (equal to 0.003). Some deviation of the superimposed structures was observed in the region of the hydrophilic amine group only. For a more quantitative description of the structural differences of both drugs we

also

Fig. 2. A superimposition of the crystal structures lidocaine hydrochloride and mexiletine hydrochloride.

of

307 (1994) 35-46

determined the intermolecular distances . . .O) specifying the separation of the two R(N polar groups, which were able to interact with the corresponding binding sites of the cardiac membrane. For lidocaine hydrochloride this distance was equal to 2.97.A. A somewhat shorter R(N . . . 0) = 2.74A length was found for mexiletine hydrochloride. The small differences between the two interaction centres indicates that a receptor which binds all of those agents must undergo only small conformational changes. (The crystal structure of tocainide hydrochloride has not been determined, according to our knowledge, till now. However, because tocainide is closely related to lidocaine, their structural features should be very similar.) For a more detailed characterization of the antiarrhythmics studied the calculated physicochemical parameters (partition coefficients, molar refractions, proton affinities and dipole moments), together with the available experimental data, are shown in Table 1. The calculated log P values, using the hydrophobic atomic parameters defined by Crippen and co-workers [26], are in a good agreement with the published experimental data. Tocainide was computed to be the most hydrophilic drug. The other computed bulk parameter, molar refraction, represents dispersion or polar interaction. These parameters, however, do not correlate with the potency of the drugs under study. It is well known that tocainide (and also mexiletine) are more potent antiarrhythmics than lidocaine [27]. However, the hydrophobicity [28] of the Ib category of antiarrhythmics significantly contributes to their potency, because it improves their penetration through hydrophobic phospholipid parts of membranes. The interaction sites of these drugs are assumed to be proteins of the sodium channel [2-41. The hydrophilic domains of c-w-helicesof channel proteins contain negatively charged residues, such as glutamic or aspartic acid, forming the inner wall of the channel, as well as N-terminal groups of proteins (arginine residues) which could serve as the binding sites for the antiarrhythmics studied. The prime

M. Remko et al./J. Mol. Strut.

39

(Theochem) 307 (1994) 35-46

Table 1 Computed partition coefficient, P, molar refraction, MR, proton affinity, PA, dipole moment, ~1,and experimental pK, of drugs under study Drug

Lidocaine Tocainide Mexiletine

log P

MR

Exp.

Calc.

2.42a

2.41 1.31 2.30

2.1F

73.90 58.78 57.04

PA (kJmol_‘)

P

916.7 895.1 922.6

2.25 2.80 2.16

PK,

0’) 7.84b 7.75b 9.00b

a Ref. 37. b Ref. 38.

candidate for the interaction with the membrane is the amine group of the drug. This group could be, at the pH of the physiological medium, both protonated and unprotonated. Table 1 contains the AM1 computed proton affinities using fully optimized geometries of base and cation. This quantity is related to the electron densities at nitrogen atoms in the gaseous state [29]. Mexiletine was found to be the most basic antiarrhythmic (Table 1). The computed proton affinities qualitatively correlate with the experimental pK, values in water. In order to obtain more knowledge about the nature of the antiarrhythmic-receptor interaction we studied these associations on model systems. The results of this investigation are presented in the following sections. Antiarrhythmic-model

membrane interactions

The complexes shown in Fig. 1 represent the most probable interactions between polar parts of antiarrhythmics and associative sites of the membrane. The hydrophilic amine part of the drug is modelled by trimethylamine, methylamine and their protonated cations. The second polar group of the drug (an ether in the mexiletine and an amide of the lidocaine and tocainide) is represented by dimethyl ether and N-methylacetamide, respectively. The associative sites of the protein part of the channel are the charged carboxylate and amine groups as well as the neutral -NHCOpeptide group (modelled by the HCOO-, CHsNHz and NH&HO species). The phosphate

group of the phospholipid is represented by the simple compound phosphate monoanion. The optimized geometries of the various complexes are summarized in Table 2 together with their binding energies AE corrected for the basis set superposition error (AE(BSSE)). This correction was smallest (about 5%) for the charged systems l-4 and 6-8. For a neutral hydrogen bond (complex 5) the correction was somewhat higher (15O/,) but, compared with the STO-3G minimal basis set calculations of the hydrogen bonds [30,31], it is still rather small. Complexes l-4 model the interaction of cationic tertiary amine and primary amine groups of the lidocaine, tocainide and mexiletine with ionized COO- and NH: groups of the lipoprotein, as well as ionized phosphate (PO;) units of the lipid part of the membrane. Our calculations show that the cationic amine group forms very strong hydrogen bonds (440-640 kJ mol-‘) with the anionic receptor site complexes la, 2a, 3a, 4a (Table 2). In those systems the bond length N+-H separating the H-bonding proton from the N atom is held fixed at the MINI-l optimized value. Motion of the proton along the C-O-. . .+H-N and P-O- .. .+H-N hydrogen bonds in 1, 2, 3 and 4, leads to the release of an additional 40-100 kJmol_’ in the neutral 0-H.. . N complexes lb, 2b, 3b and 4b leaving those systems more stable than the corresponding original isolated pairs of ions (Table 2). The occurrence of proton transfer in the four systems, 1-4, is not surprising with regard to the absolute

M. Remko et al.lJ. Mol. Struct. (Theochem)

40 Table 2 The optimized geometries and interaction

energies of the complexes studied (Fig. 1)

Complex

la lb 2a 2b 3a 3b 4a 4b 5 6 7 8 9 10

307 (1994) 35-46

(CHs)sNH+ . .- OCOH” (CHs)sN. . HOCOH (CH&NH+ .- OPO(OH); (CHs)sN . . HOPO(OH)2 (CHs)H2NH+. .- OCOHa (CH3)H,N.. HOCOH (CHs)H,NH+. .- OPO(OH)f (CHs)H,N.. HOPO(OH)z (CHs)H,N . HNHCHO (CH3)HzNH+. O=CHNH, (CHs)zO .+ NHN2(CHs) CH,NH(CHs)C=O.. .+ HNH&H, (OH)zOPO. Na+ (OH)20PO-. K+

R(A)

r (A)

o (deg)

AEHB (kJmol_‘)

AEns (BSSE) (kJ mol-‘)

2.371 2.371 2.371 2.371 2.359 2.359 2.379 2.379 2.945 2.629 2.579 2.609 1.950 2.350

l.071b 1.341 l.071b 1.321 1.029b 1.329 1.02gb 1.379 0.995 1.069 1.129 1.079

127.5 127.5 157.0 157.0 128.0 128.0 168.0 168.0 105.0 165.0 124.4 155.0

543.2 611.6 458.9 502.1 554.9 658.8 464.6 546.9 35.4 119.1 146.3 134.3 543.1 441.4

519.8 588.2 438.3 481.5 533.8 637.7 448.8 531.1 29.9 114.9 138.4 129.9 492.1 405.8

a Complexes la, Za, 3a and 4a are not true minima, but transform without barrier to lb, Zb, 3b and 4b, respectively. b r(NH) was taken from the optimized isolated (CH3)sNH+ and CH,NH: monomers.

magnitude of the MINI-l calculated proton affinities for the interacting subsystems [8,32,33]. The interaction between the ions PO, and physiological cations Na+ and Kf is also very strong (Table 2). Complexes 9 and 10 represent the shielding of the phosphate groups of phospholipids in the membrane by small cations. The energy of such complexes is comparable with the hydrogen bond energy computed for systems 2 and 4. Hence, during their interaction with phospholipids, antiarrhythmics must compete with small cations, present in vivo and forming strong bonds to phosphate groups. The primary amine group of the antiarrhythmic forms substantially stronger complexes with the carboxylate and phosphate groups than the tertiary one. This difference is probably associated with the more acidic nature of a protonated primary amine in comparison with a tertiary amine. Since lidocaine, tocainide and also mexiletine have very similar molecular structures it is possible that the different hydrogen bonding capacity of the primary amine group (e.g. in tocainide and mexiletine) in comparison with the analogous tertiary NH+ group (e.g. in lidocaine) may be, among other factors, connected to their

presumed different duration of activity in clinical application. Complexes 5 and 6 represent the interaction of neutral and ionized amine groups, respectively, with the -NHCOpeptide part of the lipoprotein domain of the membrane. The interaction for system 6 is also very strong (114.9 kJmol_‘) because of the charge on the amine. The interaction of a pair of neutral molecules, (CHs)H*N . - . HNHCHO, which may serve as the model of the protein un-ionized antiarrhythmic interaction, represents a much weaker complex. The energy of this complex is, however, higher than in the formamide dimer [33] (20.0 kJ mol-‘). Thus the antiarrhythmic molecule, either in its ionized or un-ionized state, interacts more strongly with the peptide group than does a second peptide, suggesting that the antiarrhythmic is capable of disrupting the normal interpeptide hydrogen bond pattern between or within proteins. The ether and amide groups of mexiletine, lidocaine and tocainide are further associative sites capable of forming hydrogen bonds, e.g. with -NH; groups of the arginine residues of a membrane protein [34]. Complexes 7 and 8 represent a first approximation to such bonding.

M. Remko et al/J. Mol. Struct. (Theochem) 307 (1994) 35-46

41

Of the two polar groups studied, the ether forms a stronger complex with an ionized primary amine. The energies of complexes 7 and 8 are, however, much lower (138.4 and 129.3 kJmol_‘, respectively) than the analogous hydrogen bonds formed by the amine group of the antiarrhythmic (Table 2). On the basis of our molecular modelling studies of the interactions of the polar groups of lidocaine, tocainide and mexiletine, with the associative sites in the cardiac membrane, the bonding of drug to receptor can be explained according to the dynamic two-centre zipper model (Fig. 3). According to this

model the drug binds to the receptor in two steps. In the first step the charged group of the thermodynamically preferred conformation of drugs binds to the negatively charged COO- part of the membrane. In this step recognition of the antiarrhythmic by the receptor takes place. This group forms a strong hydrogen bond with the negatively charged COO- group in which the long range electrostatic interaction predominates. In the next step (Fig. 3) it comes (with respect to the given flexibility of these drugs) to an eventual rearrangement and following interaction by means of a second interaction site (oxygen atom) resulting in the creation of the O...HN (or O...+HN) hydrogen bond. The energy of this interaction is, according to our ab initio calculations, substantially lower. However, for the detailed knowledge of the molecular arrangement of the antiarrhythmic on the membrane it is necessary to know the structural data of the receptor. Such data are lacking until now for these drugs, so our dynamic model (Fig. 3) may be considered as a first attempt to explain the action of these drugs at the molecular level and may help to discover the essential structure of the Ib class antiarrhythmic receptors.

Ar’dcHz \ d-i,C”, MEXILETINE

I

“-$I+

0-l

Proton transfer

RECEPTOR

Fig. 3. A two-centre dynamic model for the interaction the mexiletine cation at the antiarrhythmic receptor.

of

As discussed in the foregoing section, the proton can transfer in the isolated systems l-4 (Fig. 1) without an energy barrier from the drug to the receptor. However, from the point of view of pharmacology this is an undesirable situation by which a drug acts as a proton feeder of the membrane. At this point we must emphasize that our calculations pertain explicitly to the gas phase. When these complexes are placed within the context of their proper biological environment, surrounded by. membrane, protein and/or water, the situation is likely to change considerably. The interactions between physiological ions and different organic groups are of fundamental importance for the functioning of ion channels. In order to understand the behaviour of the

42

M. Remko et al./J. Mol. Struct. (Theochem,j 307 (1994) 35-46

modelled antiarrhythmic-receptor complexes in real situations of their binding in ion channels we also investigated the influence of small cations (II+, Li+, Naf) on the interaction of the charged amine group of the drug with the ionized carboxylate group of the membrane. This system forms the strongest hydrogen bond among the complexes studied (Table 2). The 3-21G optimized geometries of the systems investigated (Fig. 4) are summarized in Table 3, together with their binding energies AEna. For the isolated system 1 (Table 2), the optimized configuration corresponds to the structure which is stabilized by the electrostatic attraction of the negatively charged oxygen atoms and the cationic amine group of the subsystems. Introduction of the small cations to this system results in a considerable configurational change. For complexes 2-4 (Table 3) the stable configuration corresponds to the structures in which the amine group of the complex is rotated by 180” about the hydrogen-bonded N’-H group (Fig. 4). In that arrangement the positively charged

X+ (X’ = H, Li, Na) and NH: groups are oriented in a way that minimizes their mutual repulsion. As seen from Table 3, the smallest perturbation of the geometry of the isolated system is caused by the H+ ion. The effects of Li+ and Naf cations on the configuration of the complex are, regardless of their different size and different computed 0 +a. X+ distances (Table 3), practically identical. The net effect of the shielding of the COO- group through the ions studied is a considerable reduction of the hydrogen-bond energy Ena (Table 3) in comparison with the isolated system. To visualize the specific effects of investigated cations on the strength of isolated complexes we calculated net stabilization energies (ENS) [35] which describe the influence of ions on the stability of hydrogen bonds. The computed ENS values are shown in Table 3. Negative ENS values correspond to less stabilized hydrogen bonds. The coordination of ions to the oxygen of the proton accepting carboxylate group leads to considerable destabilization of O- . . .+ HN hydrogen bonds. The relative order of ion influence

HFI \ it;’

s

H/ ‘CH s f-q.’

\=.

F H

-0’

J

R

CHS

LO \

H

/

H

‘CH,

Fig. 4. Molecular structure of the ion-coordinated

and hydrated complexes.

M. Remko et d/J.

Table 3 Optimized geometry and interaction

energy of the complexes investigated

System

1 2 3 4

43

Mol. Struct. (Theochem) 307 (1994) 35-46

HCO; . .+ HNI-12CH3 (HCO; . .+ HNHzCHr)H+ (HCO; . . .+ HNHzCHx)Li+ (HCO; . . .+ HNH2CH3)Na+

1.413 1.380 1.349 1.331

(Fig. 4)

ro...x (A)

;deg)

AEua (kJ mol-‘)

AEHB (BSSE) (kJ mol-‘)

ENSa (kJmol_‘)

0.957 1.641 1.987

101.6 190.5 150.9 151.7

556.8 127.5 186.4 211.1

512.2 108.6 167.2 190.9

-403.6 -345.0 -321.3

a ENS = AEua(1) - AE,,.

on hydrogen bond destabilization ENS

>> &s(Li+)

is:

> ENS (Na+)

The results of the calculations on the proton potential functions for the proton transfer in the C-O- . +++H-N hydrog en bond of the formate anion-methylamine cation system is shown in Fig. 5. The proton was shifted along the axis connecting the nitrogen and oxygen atoms, and the transfer was assumed to take place at a fixed intermolecular separation R(0 91. N) = 2.75 A [9]. The calculated proton potential function for the isolated system HCOO- . - -+ HNH&H, (Fig. 5) shows two minima. The absolute minimum

-5.00

(

0.60

0.80

1.00

1.20

1.40

1.60

1.80

Ro...n*

2.00 A

Fig. 5. Proton potential function for transfer of the central proton in HCOO- . . .+ HNHzCHs (+), (HCOO- . . . +HNH&H,)H (8), (HCOO- . I -+ HNHaCHs)Li+ (e) (A) systems. and (HCOO- . . .+ H~*CH~)Na+

corresponds to the neutral 0-H.. +N bond, which is in agreement with the calculated proton affinities of both subsystems 191.The coordination of H+, Li+, and Na’ preferentially stabilizes the ion pair over its neutral analogue (Fig. 5). The strongest effect on the proton position in the hydrogen bond is exhibited by the Hf ion. A potential energy curve with only one minimum, corresponding to the O- . . .+ HN bond, has been computed. The second minimum appears with the introduction of larger cations and the weakening of the cation-subsystem interactions (Table 4). This minimum is observed as a shoulder in the (HCOO- - - -+ HNH~CH~)Li~ system (Fig. 5). The computed proton transfer curves (Fig. 5) showed that the ions in the vicinity of a hydrogen bond produced large perturbations in the proton transfer potential. For the carboxylatecationic amine complexes the presence of cations at the proton acceptor group resulted in an unambiguous stabilization of the charged O- . . -+ HN hydrogen bonds, and protonation of the drug was favoured over protonation of the receptor. In order to investigate the influence of solvent (water) on the proton transfer process we also computed for the most stable complex, 3 (Fig. l), the proton transfer potential curves corresponding to the complex hydrated by four water molecules (Fig. 4). These calculations were performed using the MINI-l basis set. For the isolated complex HCOO- a. .+ HNH2CH3 the potential energy curve showed only one minimum (Fig. 6). This minimum corresponded to the neutral 0-H. . SN hydrogen bond. The second minimum,

M. Remko et a1.l.l. Mol. Struct. (Theochem)

44

307 (1994) 35-46

Table 4 Values of binding energies, AE,, of cations to the anionic group in the systems studied (Fig. 4) System

1 2 3

(kJmol_‘)

AE, (BSSE) (kJ mol-‘)

1023.0 434.9 331.9

998.8 383.7 278.2

AEI

(HCO; (HCO; (HCO;

.+ HNH&Hs)H+ .+ HNH$Hs)Li+ .+ HNH&Hs)Na+

corresponding to the ion pair structure 3a (Table 2) was observed as a shoulder of the proton potential curve. In order to model the influence of water on the stability of various boundary hydrogen bonded structures of system 3 (Fig. l), we also investigated the proton transfer in the complex hydrated by four water molecules, as depicted in Fig. 4. The calculations were carried out with the MINI-l optimized water geometry [36], only O...O and N...O lengths being varied. Solvation of the methylamine N-H groups was considered by two water molecules oriented in a way that their Cz symmetry axis was coincident with the N-H bond. Optimized values of the 0 . ..O and N... 0 distances were 2.75 and 2.79& respectively. The fourth water molecule was oriented perpendicularly to the O-C-O plane and the 0. . -0 optimized distance was equal to 2.85A. The inclusion of four water 195.00

AE

kJ/mol

Ro...H’ A Fig. 6. Proton transfer potentials for HCOO- ... +HNH$Hs: (A) isolated system, (0) system hydrated by four waters; Rc~..,~) = 2.75 A.

molecules into the calculation of the proton transfer curves did not change the relative stability of calculated minima for the isolated system, but hydration caused considerable lowering of the second minimum (about 140 kJ mol-‘). The neutral hydrogen bond of the hydrated complex was still more stable by 9.5 kJmol-’ than the charged N-H+ . . .- OOC system. Conclusions

In this study we have taken the first steps towards constructing a molecular model for the interaction of antiarrhythmics of lidocaine type at the antiarrhythmic receptor. The results of our molecular modelling studies of the interaction of polar groups of drugs with the model sites (COO-, PO,, NH; and NHCO) of cardiac membrane lead to the following conclusions. (1) The structural similarity of lidocaine, tocainide and mexiletine resulting from the molecular modelling studies indicates that a receptor which binds all of these agents must undergo only small conformational changes. (2) The strongest interaction is of the ion-pair type and occurs between the primary and tertiary amine and the formate and phosphate groups. The COO- group is a better proton acceptor for cationic amine groups than the PO, group. (3) The primary amine group of drugs forms substantially stronger complexes with the COO- and PO; groups than the tertiary one. (4) The hydrophilic amine group interacts (in its neutral and ionized forms) with the peptide group more strongly than any peptide. (5) The ether and amide groups of mexiletine, lidocaine and tocainide form strong hydrogen

M. Remko et al./J. Mol. Struct. (Theo&m)

45

307 (1994) 35-46

bonds with ionized primary amine groups of the membrane. (6) The large dserences in stabilization energies of protonated amine part and neutral ether and amide groups of drugs studied with association sites of receptor models indicate that complex formation is favoured with the protonated species. The first step of a two-centre zipper model is the bonding of the drug to the negatively charged COO- group of the membrane, In the next step it interacts at a second interaction site (oxygen atom) of the antiarrh~hmic with the -NH;! or -NH; groups of the membrane. proton in the isolated (7) The central NH+. . .- 0 hydrogen bonds of the ionized amine-carboxylate group is transferred from the amine part to the membrane without any of cations energy ” barrier. The coordination H’, Li’, and Na+ to the C-G group of these complexes leads to a dramatic reduction in the hydrogen bond energy and a considerable change of the optimal geometry. For carboxyiate complexes with cationic amine the presence of cations at the proton acceptor group results in a considerabfe stabilization of the charged O- . . +9HN hydrogen bonds. The calculations in this work were primarily considered as a tool for understanding possible interactions of polar groups of antiarrhythmics with their complementary bonding sites in the cardiac membrane. The two-centre dynamic model derived on the basis of these results may be useful for further investigations of the mechanisms of antiarrhythmics actions at the molecular level.

We thank Dr. J. Sivy for technical assistance and interest. Support of this work from the Austrian Federal Ministry for Science and Research (Grant GZ.45.21 l/2-27b/91) and from the Slovak Ministry of Education (Grant No. l/6/93) are gratefully acknowledged. S.S. acknowledges NIH grant GM29391.

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