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Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods

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Summary

Methylphenidate (MP) binds to the cocaine binding site on the dopamine transporter and inhibits reuptake of dopamine, but does not appear to have the same abuse potential as cocaine. This study, part of a comprehensive effort to identify a drug treatment for cocaine abuse, investigates the effect of choice of calculation technique and of solvent model on the conformational potential energy surface (PES) of MP and a rigid methylphenidate (RMP) analogue which exhibits the same dopamine transporter binding affinity as MP. Conformational analysis was carried out by the AM1 and AM1/SM5.4 semiempirical molecular orbital methods, a molecular mechanics method (Tripos force field with the dielectric set equal to that of vacuum or water) and the HF/6-31G* molecular orbital method in vacuum phase. Although all three methods differ somewhat in the local details of the PES, the general trends are the same for neutral and protonated MP. In vacuum phase, protonation has a distinctive effect in decreasing the regions of space available to the local conformational minima. Solvent has little effect on the PES of the neutral molecule and tends to stabilize the protonated species. The random search (RS) conformational analysis technique using the Tripos force field was found to be capable of locating the minima found by the molecular orbital methods using systematic grid search. This suggests that the RS/Tripos force field/vacuum phase protocol is a reasonable choice for locating the local minima of MP. However, the Tripos force field gave significantly larger phenyl ring rotational barriers than the molecular orbital methods for MP and RMP. For both the neutral and protonated cases, all three methods found the phenyl ring rotational barriers for the RMP conformers/invertamers (denoted as cte, tte, and cta) to be: cte, tte> MP > cta. Solvation has negligible effect on the phenyl ring rotational barrier of RMP. The B3LYP/6-31G* density functional method was used to calculate the phenyl ring rotational barrier for neutral MP and gave results very similar to those of the HF/6-31G* method.

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Abbreviations

AM1:

Austin Model

SM5.4:

Solvent Model, parameterization 5.4

MP:

methylphenidate

RMP:

rigid methylphenidate

nMP:

neutral methylphenidate

pMP:

protonated methylphenidate

nRMP:

neutral rigid methylphenidate

pRMP:

protonated rigid methylphenidate

QSAR:

quantitative structure-activity relationships

RMSD :

root mean square deviation

RS:

random search

SAR:

struc-ture-activity relationships

CoMFA:

Comparative Molecular Field Analysis

DAT:

dopamine transporter

PES:

potential energy surface

HF/6-31G*:

Hartree-Fock 6-31G* basis set. For the RMP notations: cte (ring cistrans stereochemistry, phenyl group equatorial), tte (ring trans, trans stereochemistry, phenyl group equatorial), and cta (ring cis, trans stereochemistry, phenyl group axial).

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Authors and Affiliations

  1. Department of Chemistry and Environmental Science, New Jersey Institute of Technology, 323 King Blvd., Newark, NJ 07102, USA

    Kathleen M. Gilbert, William J. Skawinski, Milind Misra, Kristina A. Paris, Neelam H. Naik, Ronald A. Buono & Carol A. Venanzi

  2. School of Chemistry and Biochemistry, Georgia Institute of Technology, 30332-0400, Atlanta, GA, USA

    Howard M. Deutsch

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  1. Kathleen M. Gilbert
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  2. William J. Skawinski
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  3. Milind Misra
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Correspondence to Carol A. Venanzi.

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Gilbert, K.M., Skawinski, W.J., Misra, M. et al. Conformational analysis of methylphenidate: comparison of molecular orbital and molecular mechanics methods. J Comput Aided Mol Des 18, 719–738 (2004). https://doi.org/10.1007/s10822-004-7610-1

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