Molecular modeling of multi-target analogs of huperzine A and applications in Alzheimer's disease.

CONTEXT: Given the diverse pathophysiological mechanisms underlying Alzheimer's disease, it is improbable that a single targeted drug will prove successful as a therapeutic strategy. Therefore, exploring various hypotheses in drug design is imperative. The sequestration of Fe(II) and Zn(II) cations stands out as a crucial mechanism based on the mitigation of reactive oxygen species. Moreover, inhibiting acetylcholinesterase represents a pivotal strategy to enhance acetylcholine levels in the synaptic cleft. This research aims to investigate the analogs of Huperzine A, documented in scientific literature, considering of these two hypotheses. Consequently, the speciation chemistry of these structures with Fe(II) and Zn(II) was scrutinized using quantum chemistry calculations, molecular docking simulations, and theoretical predictions of pharmacokinetics properties. From the pharmacokinetic properties, only two analogs, HupA-A1 and HupA-A2, exhibited a theoretical permeability across the blood-brain barrier; on the other hand, from a thermodynamic standpoint, the enantiomers of HupA-A2 showed negligible chelation values. The enantiomers with the most favorable interaction parameters were S'R'HupA-A1 (ΔGBIND = -40.0 kcal mol-1, fitness score = 35.5) and R'R'HupA-A1 (ΔGBIND = -35.5 kcal mol-1, fitness score = 22.61), being compared with HupA (ΔGBIND = -41.75 kcal mol-1, fitness score = 39.95). From this study, some prime candidates for promising drug were S'R'HupA-A1 and R'R'HupA-A1, primarily owing to their favorable thermodynamic chelating capability and potential anticholinesterase mechanism. METHODS: Quantum chemistry calculations were carried out at B3LYP/6-31G(d) level, considering the IEF-PCM(UFF) implicit solvent model for water. The coordination compounds were assessed using the Gibbs free energy variation and hard and soft acid theory. Molecular docking calculations were conducted using the GOLD program, based on the crystal structure of the acetylcholinesterase protein (PDB code = 4EY5), where the ChemScore function was employed with the active site defined as the region within a 15-Å radius around the centroid coordinates (X = -9.557583, Y = -43.910473, Z = 31.466687). Pharmacokinetic properties were predicted using SwissADME, focusing on Lipinski's rule of five.

S-Se oxidative addition to auranofin derivatives: a DFT study.

Oxidative addition of the S-Se bond to Au(I) complexes is discussed for a series of 26 auranofin (AF) derivatives. AF and its analogues are Au(I) complexes with recognized anticancer activity that act by binding and inhibiting the thioredoxin reductase (TrxR) enzyme. Generally, the oxidative addition to Au(I) is a sluggish reaction under mild conditions (i.e., a high activation barrier - ΔH‡), which is also verified here for AF, ΔH‡ = 33.0 kcal mol-1. However, we predicted that subtle changes in the AF ligands can make the process feasible under standard conditions. For instance, the exchange of -PEt3 by -P(Et2)(OEt), which is a weaker electron σ-donor, reduced the activation barrier to 17.1 kcal mol-1. Furthermore, substitution of the -SAtg ligand by -Cl- leads to a ΔH‡ value of 22.5 kcal mol-1. Overall, the reaction is driven by the nucleophilic attack of the S-Se bond on the Au(I) center, attributed mainly to the charge transfer (4p)Se → (6p)Au, which characterizes the addition step. At the transition state (TS) point, the (5d)Au → σ*(S-Se) charge transfer becomes relevant, facilitating the S-Se bond breakage and the oxidation step. In addition to the electron transfers, the strain energy to deform the linear Au(I) geometry to the tetracoordinated Au(III) arrangement in the TS structure plays a primary role in explaining the trends in the activation barriers. Finally, the activation barrier (ΔH‡) and reaction energy (ΔH°) were correlated for most of the complexes studied, which suggests that the reaction passes through a late or product-like TS and, therefore, the steric and electronic factors affecting ΔH‡ also act on ΔH°. Overall, the results presented here might open up a new field of investigation for interactions between AF derivatives and TrxR, which contributes to a full understanding of the biological mechanism of action of these species.

An investigation of the predominant structure of antibiotic azithromycin in chloroform solution through NMR and thermodynamic analysis.

Azithromycin (AZM) is a well-known macrolide-type antibiotic that has been used in the treatment of infections and inflammations. Knowledge of the predominant molecular structure in solution is a prerequisite for an understanding of the interactions of the drug in biological media. Experimental structural determination can be carried out for samples in solid-state (X-ray diffraction technique) and gas phase (electron diffraction experiment). In solution, spectroscopic methods can be used to extract valuable information which combined with quantum chemical calculations can lead to the determination of the preferred molecular structures to be observed when a given solute is dissolved in each solvent. That is precisely the aim of this work. We used experimental NMR chemical shift data (in CDCl3) as a reference for comparison with Density Functional Theory (DFT) NMR calculations, with geometry optimized having as guess input two crystallographic structures available in the literature with the configuration of all chiral carbon atoms inverted, named here A and B. The Polarizable Continuum Model (PCM) was used to describe the solvent effects (chloroform) including five explicit CHCl3 solvent molecules, which we believe can account for short and long-range solute-solvent interactions. Analysis of calculated thermodynamic, NMR chemical shift, MAE (Mean Absolute Error), and spin-spin coupling constant values revealed that both supposable C3R-C5S (named M2-A) and C3S-C5R (named M2-B) structures are equally probable to exist in chloroform solution. In addition, we found that the heavy atoms' conformation is reasonably similar in the solid-state and chloroform solution; however, regarding the OH groups, the spatial orientations are rather different with intramolecular OH⋯N and OH⋯O hydrogen bonds present in solution and with some of them being absent in the X-ray structure probably due to crystal packing effects.

The role of tridentate ligands on the redox stability of anticancer gold(III) complexes.

Gold(III) complexes are promising compounds for cancer chemotherapy, whose action depends on their redox stability. In this context, the choice of ligands is crucial to adjust their reactivity and biological response. The present study addressed the effect of the gold coordination sphere on the reduction potential (Eo) for ten gold(III) complexes containing five or six-membered rings tridentate ligands - [AuIII(trident)Cl]3+n (trident = N^N^N, C^N^N, C^C^N, C^N^C, and N^C^N). The calculated Eo covered a broad range of 2500 mV with the most stable complexes containing two AuC bonds (Eo = -1.85 V for [AuIII(C^C^N)Cl] - f). For complexes with one AuC bond, the N^C^N ligands stabilize the gold(III) complex more efficiently than N^N^C; however, the inclusion of the non-innocent ligand bipy (2,2'-bipyridine) in N^N portion provides an extra stabilization effect. Among the derivatives with one AuC bond, [AuIII(N^N^C)Cl]+ (N^N = bipy) (a) showed Eo = -1.20 V. For the complexes with N^N^N ligands, Eo was positive and almost constant (+0.60 V). Furthermore, the kinetics for ligand exchange reactions (Cl-/H2O, H2O/Cys and Cl-/Cys) were monitored for the most stable compounds and the energy profiles compared to the reduction pathways.

Computational Prediction of Tc-99 NMR Chemical Shifts in Technetium Complexes with Radiopharmaceutical Applications.

The Tc-99m nucleus is the most used nuclide in radiopharmaceuticals designed for imaging diagnosis. The metal can exist in nine distinct oxidation states and forms distinct coordination complexes with a variety of chelating agents and geometries. These complexes are usually characterized through Tc-99 NMR that is very sensitive to the Tc coordination sphere. Therefore, predicting Tc-99 NMR might be useful to assist experimentalists in structural characterization. In the present study, we propose three computational protocols for predicting Tc-99 NMR chemical shifts based on density functional theory calculations using relativistic and nonrelativistic Hamiltonians: the relativistic Model 1, the nonrelativistic Model 2, and the empirical nonrelativistic Model 3. In Models 2 and 3, the NMR-DKH basis set was used for all atoms, including the Tc, for which it was developed here. All models were applied for a set of 41 Tc-complexes with metal oxidation states 0, I, and V, for which the Tc-99 chemical shift was available experimentally. The mean absolute deviation and the mean relative deviation were 67 ppm and 4.8% (Model 1), 92 ppm and 6.2% (Model 2), and 65 ppm and 4.9% (Model 3), respectively. Last, the effect of the explicit solvent was evaluated for the [TcO2(en)2]+─Tc(V) complex. The calculated results for the Tc-99 NMR chemical shift at SO-ZORA-SSB-D/TZ2P-ZORA/COSMO//TPSS/def2-SVP/IEF-PCM(UFF) show that the inclusion of 14 water molecules (first solvation shell) together with the implicit solvation model leads to an absolute deviation of only 7 ppm (0.3%) from the experimental value, indicating that the solvent effects play a key role in predicting Tc-99 NMR.

Antivirals virtual screening to SARS-CoV-2 non-structural proteins.

In March 2020, the World Health Organization (WHO) declared coronavirus disease-19 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. Since then, the search for a vaccine or drug for COVID-19 treatment has started worldwide. In this regard, a fast approach is the repurposing of drugs, primarily antiviral drugs. Herein, we performed a virtual screening using 22 antiviral drugs retrieved from the DrugBank repository, azithromycin (antibiotic), ivermectin (antinematode), and seven non-structural proteins (Nsps) of SARS-CoV-2, which are considered important targets for drugs, via molecular docking and molecular dynamics simulations. Drug-receptor binding energy was employed as the main descriptor. Based on the results, paritaprevir was predicted as a promising multi-target drug that favorably bound to all tested Nsps, mainly adipose differentiation-related protein (ADRP) (-36.2 kcal mol-1) and coronavirus main proteinase (Mpro) (-32.2 kcal mol-1). Moreover, the results suggest that simeprevir is a strong inhibitor of Mpro (-37.2 kcal mol-1), which is an interesting finding because Mpro plays an important role in viral replication. In addition to drug-receptor affinity, hot spot residues were characterized to facilitate the design of new drug derivatives with improved biological responses.

Vibrational frequencies and intramolecular force constants for cisplatin: assessing the role of the platinum basis set and relativistic effects.

The role of platinum basis set (PTBS) and relativistic effects for predicting the vibrational frequencies and intramolecular force constants for cisplatin are discussed. Nonrelativistic and relativistic computational protocols were built at B3LYP/PTBS/jorge-DZP/C-PCM and B3LYP-DKH2/PTBS/jorge-DZP-DKH/C-PCM levels, respectively, where 19 distinct PTBS were tested. As expected, the structural parameters were not very sensitive to the PTBS, however, the inclusion of relativistic effects improves the description of the cisplatin structure. When it comes to the vibrational frequencies, the results show that the PTBS, and mainly the relativistic effects, are both important. Moreover, the PBE0 functional led to better results than B3LYP in the protocols PBE0/LANL2TZ(f)/jorge-DZP/C-PCM (P20) and PBE0-DKH2/Sapporo-DKH3-DZP-2012/jorge-DZP-DKH/C-PCM (P22), which provided a mean absolute deviation (MAD) of only 10.8 cm-1 and 9.5 cm-1, respectively, for vibrational frequencies, which are excellent choices to study Pt complexes. Finally, a discussion of the intramolecular force constants for cisplatin is carried out, with the calculated bond and angles force constants with P20 and P22 protocols being recommended for the parameterization of the force field of cisplatin.

Predicting the structure and NMR coupling constant 1J(129Xe-19F) of XeF6 using quantum mechanics methods.

The XeF6 molecule exists as a monomer in the gas phase and as the (XeF6)4 tetramer in solution. Herein we used distinct quantum mechanics methods to study the conformational equilibrium for the XeF6 monomer, which is represented mainly by Oh and C3v symmetric geometries, and for the (XeF6)4 structure found in condensate phases. The NMR 1J(129Xe-19F) coupling constant is predicted using our own NMR-DKH basis set, designed for NMR properties. The C3v conformer of XeF6 was stable only with HF, CCSD, and hybrid DFT functionals with at least 28% exact HF exchange. Increasing the % of HF exchange improves the description of the geometry and the Oh→C3v equilibrium. The BMK, BHandHLYP and LC-ωPBE functionals produce results in excellent agreement with experiments and high-level calculations for the XeF6 molecule. When it comes to the 1J(129Xe-19F) coupling constant, the (XeF6)4 structure must be considered. For that compound, BHandHLYP leads to the best structure, and BMK leads to the best coupling constant; therefore, the generalized protocol BMK/NMR-DKH//BHandHLYP/def2-SVP is recommended to study the XeF6 molecule in the gas phase and solution.

Role of the Enzymatic Environment in the Reactivity of the AuIII-C

The action mechanism of anticancer gold(III) complexes is a multi-step process and depends on their redox stability. First, the gold(III) complex undergoes a ligand exchange reaction in the presence of cellular thiols, such as those available in the active site of the enzyme TrxR, and then, the AuIII → AuI reduction occurs. Most experimental and theoretical studies describe these processes under chemical conditions without considering the enzyme structure effect. In the present study, molecular models are proposed for the [AuIII(C^N^C)(SHCys-R)]+ adduct, with the [AuIII(C^N^C)]+ moiety bonded to the Cys498 residue in the C-terminal arm of the TrxR. This one represents the product of the first ligand exchange reaction. Overall, our results suggest that the exchange of the auxiliary ligand (for instance, Cl- to S-R) plays a primary role in increasing the reduction potential, with the enzyme structure having a small effect. The parent compound [AuIII(C^N^C)Cl] has E° = -1.20 V, which enlarges to -0.72 V for [AuIII(C^N^C)CH3SH]+ and to -0.65 V for the largest model studied, Au-trx. In addition to the effect of the enzyme structure on the redox stability, we also analyze the Au transfer to the enzyme using a small peptide model (a tetramer). This reaction is dependent on the Cys497 protonation state. Thermodynamics and kinetic analysis suggests that the C^N^C ligand substitution by Cys497 is an exergonic process, with an energy barrier estimated at 20.2 kcal mol-1. The complete transfer of the Au ion to the enzyme's active site would lead to a total loss of enzyme activity, generating oxidative damage and, consequently, cancer cell death.

1H and 195Pt NMR prediction for inclusion compounds formed by cisplatin and oxidized carbon nanostructures.

Prediction of NMR chemical shifts can assist experimentalists in the characterization of drug delivery systems based on carbon nanocomposites. Chemical shifts are strongly correlated to the nucleus position and its chemical neighborhood. Therefore, to predict structures and NMR properties of complex chemical models, choosing a more consistent theoretical level capable of providing more realistic results and moderate computational demand is a major challenge. In this work, we predicted the NMR spectra of inclusion compounds formed by cisplatin (cDDP) and an oxidized carbon nanotube (CNTox) and nanocone (CNCox) considered by specialists as potential drug delivery systems. The 195Pt NMR chemical shifts calculated at the DFT level with the new relativistic NMR-DKH basis set were -2314 ppm and -2192 ppm for cDDP@CNTox and cDDP@CNCox complexes, respectively, which are both high-field shifted relative to the free cDDP (-2110 ppm). 1H NMR chemical shifts are also sensitive to the inclusion process. The H (NH3) signals are found on average at +4.3 (cDDP), -5.1 (cDDP@CNTox) and +6.6 ppm (cDDP@CNCox). Interestingly, despite the similar inclusion modes in CNTox and CNCox cavities, the 1H NMR shifts were in opposite directions. A possible reason might be the higher stability of cDDP@CNTox (ΔE F = -19.9 kcal mol-1) than that of cDDP@CNCox (ΔE F = -5.7 kcal mol-1), which suggests a short guest-host contact in the former and consequently, a more efficient shielding of hydrogen atoms due to the electron-rich carbon structure. These results may be helpful as comparison data in the NMR spectra assignment in solution and the inclusion compounds' structural elucidation.

Structure and redox stability of [Au(III)(X

The choice of the auxiliary ligand in Au(III) complexes is of paramount importance in tuning their reactivity and biological activity. Tertiary phosphines are one of the most used auxiliary ligands in gold compounds, due to their stereo-electronic properties that confer stability and lipophilicity to these metallodrugs. The redox stability of [Au(III)(C^N^C)PR3]+ (A) (C^N^C = 2,6-diphenylpyridine) and [Au(III)(N^N^N)PR3]3+ (N^N^N = 2,2':6',2″-terpyridine) (B) complexes (where R is the phosphine substituent groups with different steric and electronic properties) was herein investigated for a set of 41 phosphines, using the predicted standard reduction potential (εo) for Au(III)/Au(I) electrochemical system as reference. For the complexes A, εo spread over 829 mV and all values were negative, whereas for the complexes B εo were positive and covered a narrower range of 507 mV. The phosphines with high buried volume (%Vbur ≥ 32%) decrease the complex stability despite being strong σ-donors. Both steric and electronic properties were used as molecular descriptors to build quantitative structure-property relationships (QSPR), which showed that the %Vbur plays the major role on the redox stability of the studied Au(III) complexes. For complexes B where the phosphine affects both Au(III) and Au(I) forms, the steric impact is more pronounced on the Au(I) reduced species. The electron-donating ability of phosphines is also important and plays a greater role on the redox stability of complexes B than complexes A. These outcomes are certainly useful to predict the redox stability of Au(III) complexes which, in turn, should affect their chemical reactivity against biological targets.

Simultaneous determination of aspartame, cyclamate, saccharin and acesulfame-K in powder tabletop sweeteners by FT-Raman spectroscopy associated with the multivariate calibration: PLS, iPLS and siPLS models were compared.

For the first time, a procedure for simultaneous determination of the main artificial sweeteners, aspartame (ASP), cyclamate (CYC), saccharin (SAC), and acesulfame-K (ACSK) by a spectroscopic method associated with the multivariate calibration is proposed. These analytes were quantified in tabletop sweeteners samples using FT-Raman spectroscopy. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used as reference method. Partial least squares (PLS), interval PLS (iPLS), and synergism PLS (siPLS) methods were evaluated in a comparative study where the selected interval models presented better results. Multivariate regression models, such as PLS, iPLS and siPLS were built and the lower root mean square errors for prediction (RMSEP) found were 0.027-0.031% w/w, 0.316-0.363% w/w, 0.082-0.184% w/w, and 0.040-0.049% w/w to ASP, CYC, SAC, and ACSK, respectively. The coefficient of determination for prediction (R2p) varied between 0.978 and 0.979, 0.969-0.977, 0.952-0.994, and 0.959-0.965 for ASP, CYC, SAC and ACSK, respectively. The analysis of model's residues was made by bias and permutation tests to evaluate systematic and trend errors. The selected intervals by iPLS and siPLS were evaluated and the bands related to the vibrational modes of the analytes were assigned with the aid of density functional theory calculations (DFT).

Non-centrosymmetric crystals of new N-benzylideneaniline derivatives as potential materials for non-linear optics.

Three new N-benzylideneaniline derivatives [p-nitrobenzylidene-p-phenylamineaniline (I), 2,4-dinitrobenzylidene-p-phenylamineaniline (II) and p-dinitrobenzylidene-p-diethylamineaniline (III)] containing electron-push-pull groups have been prepared. They present a planar N-benzylideneaniline core and neighbouring functional atoms, which are related through an efficient intramolecular charge transfer (CT). Two of the derivatives crystallize in non-centrosymmetric space groups, a necessary condition for non-linear optical (NLO) responses. The NLO properties were calculated for the molecular conformations determined by single-crystal X-ray diffraction as well as for the four molecules packed into each corresponding unit cell, using a quantum-chemical method at the cam-B3LYP/NLO-V level of theory. As expected from antiparallel face-to-face stacking through centrosymmetry, the main NLO descriptors - namely, the first hyperpolarizability (ßtot) and its projection on the dipole moment direction (ßvec) - are almost zero for the tetramer of derivative III. Interestingly, the calculated first hyperpolarizability decreases in the non-centrosymmetric unit-cell content of derivative II when compared to its single molecule, which may be related to its molecular pillaring, similar to that observed in derivative III. On the other hand, a desirable magnification of the NLO properties was found for packed units of derivative I, which may be a consequence of its parallel face-to-tail stacking with the CT vectors of all molecules pointing in the same direction. Moreover, the CT vector of compound I makes an angle of θ = 33.6° with its crystal polar axis, resulting in a higher-order parameter (cos(3)θ = 0.6) compared with the other derivatives. This is in line with the higher macroscopic second-order NLO response predicted for derivative I, ßtot = 120.4 × 10(-30) e.s.u.

Adsorption study of antibiotics on silver nanoparticle surfaces by surface-enhanced Raman scattering spectroscopy.

In this work the adsorption of the antibiotics levofloxacin (LV), tetracycline (TC) and benzylpenicillin (BP) on the surface of silver nanoparticles (AgNP) have been investigated through both surface-enhanced Raman scattering (SERS) and UV-VIS-NIR spectroscopies. The SERS spectra were obtained using 1064 nm exciting radiation. Theoretical models for the antibiotic molecules were obtained from DFT calculations, and used in the vibrational assignment. The adsorption geometries were proposed based on the changes in the spectral patterns. The LV compound adsorbs through carboxylate group, TC compound interacts with silver atoms through carbonyl from intermediate ring, and BP compound adsorbs by carbonyl moieties from carboxylate and acyclic amide.

Assessing the quantum mechanical level of theory for prediction of linear and nonlinear optical properties of push-pull organic molecules.

In this paper, we assessed the quantum mechanical level of theory for prediction of linear and nonlinear optical (NLO) properties of push-pull organic molecules. The electric dipole moment (µ), mean polarizability ([Symbol: see text]α[Symbol: see text]) and total static first hyperpolarizability (ßt) were calculated for a set of benzene, styrene, biphenyl and stilbene derivatives using HF, MP2 and DFT (31 different functionals) levels and over 71 distinct basis sets. In addition, we propose two new basis sets, NLO-V and aNLO-V, for NLO properties calculations. As the main outcomes it is shown that long-range corrected DFT functionals such as M062X, ωB97, cam-B3LYP, LC-BLYP and LC-ωPBE work satisfactorily for NLO properties when appropriate basis sets such as those proposed here (NLO-V or aNLO-V) are used. For most molecules with ß ranging from 0 to 190 esu, the average absolute deviation was 13.2 esu for NLO-V basis sets, compared to 27.2 esu for the standard 6-31 G(2d) basis set. Therefore, we conclude that the new basis sets proposed here (NLO-V and aNLO-V), together with the cam-B3LYP functional, make an affordable calculation scheme to predict NLO properties of large organic molecules.

Exploring the potential energy surface for the interaction of sterically hindered trichloro(diethylenetriamine)gold(III) complexes with water.

The reactivity of gold(III) complexes is analyzed for a series of derivatives of 3-azapentane-1,5-diamine (dien) tridentate ligand that can contain some bulky substituents. Two distinct series of compounds are considered where the dien ligand is either deprotonated (R-dien-H) or protonated (R-dien) at the secondary amine where R = ethyl (Et) or methyl (Me). While the deprotonated species will occur in neutral and basic solutions, the protonated forms are likely to be present in acidic environment. Hydration reaction (water/Cl(-) ligand exchange) of 14 complexes is modeled with quantum chemical calculations. Our calculations predict that the reactivity decreases with the increase in the molecular volume of the substituted dien ligand, and the calculated rate constants are in satisfactory agreement with experimental results. In addition, quantitative structure/reactivity models are proposed where the angle between the entering and leaving groups in the transition state structure (the reactivity angle) is used as a molecular descriptor. These models explain the trend of the relative reactivity of these complexes and can be used to design new ligands for gold(III) complexes aiming to adjust the reactivity of the complex.

The role of the basis set and the level of quantum mechanical theory in the prediction of the structure and reactivity of cisplatin.

In this article, we conducted an extensive ab initio study on the importance of the level of theory and the basis set for theoretical predictions of the structure and reactivity of cisplatin [cis-diamminedichloroplatinum(II) (cDDP)]. Initially, the role of the basis set for the Pt atom was assessed using 24 different basis sets, including three all-electron basis sets (ABS). In addition, a modified all-electron double zeta polarized basis set (mDZP) was proposed by adding a set of diffuse d functions onto the existing DZP basis set. The energy barrier and the rate constant for the first chloride/water exchange ligand process, namely, the aquation reaction, were taken as benchmarks for which reliable experimental data are available. At the B3LYP/mDZP/6-31+G(d) level (the first basis set is for Pt and the last set is for all of the light atoms), the energy barrier was 22.8 kcal mol(-1), which is in agreement with the average experimental value, 22.9 ± 0.4 kcal mol(-1). For the other accessible ABS (DZP and ADZP), the corresponding values were 15.4 and 24.5 kcal mol(-1), respectively. The ADZP and mDZP are notably similar, raising the importance of diffuse d functions for the prediction of the kinetic properties of cDDP. In this article, we also analyze the ligand basis set and the level of theory effects by considering 36 basis sets at distinct levels of theory, namely, Hartree-Fock, MP2, and several DFT functionals. From a survey of the data, we recommend the mPW1PW91/mDZP/6-31+G(d) or B3PW91/mDZP/6-31+G(d) levels to describe the structure and reactivity of cDDP and its small derivatives. Conversely, for large molecules containing a cisplatin motif (for example, the cDDP-DNA complex), the lower levels B3LYP/LANL2DZ/6-31+G(d) and B3LYP/SBKJC-VDZ/6-31+G(d) are suggested. At these levels of theory, the predicted energy barrier was 26.0 and 25.9 kcal mol(-1), respectively, which is only 13% higher than the actual value.