Flaws in foldamers: conformational uniformity and signal decay in achiral helical peptide oligomers

Although foldamers, by definition, are extended molecular structures with a well-defined conformation, minor conformers must be populated at least to some extent in solution. We present a quantitative analysis of these minor conformers for a series of helical oligomers built from achiral but helicogenic α-amino acids. By measuring the chain length dependence or chain position dependence of NMR or CD quantities that measure screw-sense preference in a helical oligomer, we quantify values for the decay constant of a conformational signal as it passes through the molecular structure. This conformational signal is a perturbation of the racemic mixture of M and P helices that such oligomers typically adopt by the inclusion of an N or C terminal chiral inducer. We show that decay constants may be very low (<1% signal loss per residue) in non-polar solvents, and we evaluate the increase in decay constant that results in polar solvents, at higher temperatures, and with more conformationally flexible residues such as Gly. Decay constants are independent of whether the signal originates from the N or the C terminus. By interpreting the decay constant in terms of the probability with which conformations containing a screw-sense reversal are populated, we quantify the populations of these alternative minor conformers within the overall ensemble of secondary structures adopted by the foldamer. We deduce helical persistence lengths for Aib polymers that allow us to show that in a non-polar solvent a peptide helix, even in the absence of chiral residues, may continue with the same screw sense for approximately 200 residues.     

Density functional theory calculations and vibrational circular dichroism of aromatic foldamers

Ab initio calculations together with vibrational circular dichroism (VCD) have been used for studying the conformations of a quinoline-derived oligoamide bearing a terminal chiral residue. Three helically folded conformers of the dimer, trimer, and tetramer forms of the oligomer were optimized at the density functional theory (DFT) level using the B3LYP functional and the 6-31G* basis set. For each form, the three conformers differ in their helical handedness and in the conformation of the chiral end group. The calculated structures of the tetramer and also the proportions predicted between them based on their calculated Gibbs free energies differences match remarkably well with experimental data collected on an octamer. Specifically, a R-phenethyl terminal group gives rise to a 91:9 ratio between left handed and right handed helices. The predicted VCD spectrum calculated from the Boltzmann population of the individual conformer reproduces very well the experimental VCD spectrum of the tetramer in CDCl3 solution. The DFT calculations performed for the trimer also allow one to assess the preferred handedness of the helix and the conformation of the chiral end group, but the calculated relative populations differ slightly from experimental data. Finally, this study shows that the dimer fragment is not sufficient to obtain valuable information on the conformation of this aromatic oligoamide foldamer.     

Conformational properties, chiroptical spectra, and molecular self-assembly of 2,3-piperazinodiones and their dithiono analogues

A family of chiral cyclic oxamides was prepared by the condensation of optically active 1,2-diamines with diethyl oxalate. Thionation of the products with Lawesson's reagent afforded a series of chiral 2,3-piperazinedithiones. Molecular geometries of the title compounds were studied with the use of quantum mechanical DFT calculations and were compared to the X-ray crystallographic results. The heterocyclic six-membered ring adopted a half-chair conformation with the C-5 substituent preferably at the equatorial position, whereas a substitution at the nitrogen atoms resulted in domination of the axial form in the conformational equilibrium. The opposite helicity of the twisted oxamide chromophore in the axial and equatorial conformers led to the opposite signs of the Cotton effects corresponding to two pi-pi* electronic transitions. The CD signs can be predicted by a simple helicity rule. The same rule is valid for 2,3-piperazinodithiones, where a substitution of sulfur for oxygen in the carbonyl groups results in bathochromic shifts of the absorption and CD bands. The crystal packing analysis of several 2,3-piperazinodiones revealed that strong NH...O=C intermolecular hydrogen-bonding interactions generating the chain motif resulted in the formation of 3-D networks as well as with the use of the cyclic hydrogen-bond motif tape structures.     

Methyl 4-O-acetyl-3-azido- and 3-azido-4-O-methylsulfonyl-2,3,6,-trideoxyhex-5- enopyranosides in DFT-level conformational studies

Geometry optimizations at the B3LYP level of density functional theory (DFT) are reported for methyl 4-O-acetyl-3-azido- and 3-azido-4-O-methylsulfonyl-2,3,6-trideoxy-alpha,beta-d-threo- and -beta-d-erythro-hex-5-enopyranosides. The most stable conformers for each compound are presented, along with the corresponding enthalpies and Gibbs free energies. The influence of the exocyclic double bond on the chair conformation is discussed. Conformations of the 1-OMe, 3-N3, and 4-OAc groups were examined, and delocalization in the OAc and N3 groups was demonstrated. The contributions of particular conformers to the total number of structures found for each hex-5-enopyranoside were calculated. The theoretical results are compared with assignments based on 1H NMR studies.     

Structural analysis of sterically hindered 1,4‐diols from the naturally occurring lignan hydroxymatairesinol a quantum chemical study

The structures of TADDOL‐like α‐conidendrin‐based chiral 1,4‐diols (LIGNOLs) have been studied at molecular mechanics, Hartree‐Fock (HF)/6‐31G* and DFT/B3LYP/TZVP level of theory. The molecules included were 1,1‐diphenyl, two diastereomers of 1,1,4‐triphenyl, 1,1,4,4‐tetraphenyl, and 1,1,4,4‐tetramethyl 1,4‐diol. Several conformers of each molecule were studied thorougly also including the entropy contributions. For the triphenyl 1,4‐diols, which can form π ? π interactions between phenyl rings, the DFT optimized structures differed significantly from the HF optimized ones. A property for the most stable structures, in addition to the ability to form π ? π interactions, seemed to be the possibility to have the aliphatic six‐membered ring in a boat conformation. For all of the studied LIGNOLs some conformers were found, where the two OH groups pointed almost to the same direction. By this an intramolecular hydrogen bond can be formed between them. The bridging hydrogen atom falls at the same place as a chelate‐bonded metal ion would be situated, as in the case of the analogous molecules, TADDOLs, but only a few of these molecules would be able to work well as ligands for asymmetric catalysis. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

From chiral counterions to twisted membranes

In membranes, the chirality of the amphiphile constituents is sometimes expressed at a supramolecular scale of nanometers or micrometers. We have recently reported that membranes of nonchiral dicationic n-2-n amphiphiles can also be chirally twisted upon interacting with chiral tartrate counterions. Here, we demonstrate that the mechanism of the chiral induction by counterions involves specific anion-cation recognition and the induction of conformationally labile chirality in the cations. Single-crystal X-ray diffraction shows that the amphiphilic cations exist as a mixture of chiral conformers. (1)H NMR data establish a specific recognition between tartrate and n-2-n cations and show that chiral conformers also exist in solution. Circular dichroism (CD) in the UV-vis shows a sharp conformational change of tartrate ions from anti to gauche when bound to the chiral cationic membranes. This is confirmed by CD in the infrared region which also shows concomitant induced CD bands in the vibrations of the n-2-n amphiphiles. These results represent the first example of the so-called Pfeiffer effect in a membrane. They provide a general framework for designing new tunable membrane systems. Our work also includes the first application of vibrational circular dichroism in the study of chiral conformations of amphiphiles in membranes and demonstrates the very high potential of this technique.     

Solvent-induced conformational changes of O-phenyl-cinchonidine: a theoretical and VCD spectroscopy study

The conformational analysis of the synthetic chiral modifier O-phenyl-cinchonidine (PhOCD) used in enantioselective hydrogenations over noble metal catalysts has been performed at a PM3 semiempirical level in vacuum. The minimum energy conformations calculated at the DFT level with a medium-size basis set have been compared to those of the parent alkaloid cinchonidine (CD). PhOCD behaves similarly to CD and shows four main conformers, denoted as Closed(1), Closed(2), Open(3), and Open(4). Open(3) is found to be the most stable in vacuum and in CH2Cl2 and CCl4 solvents. A comprehensive normal-mode analysis has been performed for these conformers, and assignment of the infrared spectrum of PhOCD in CCl4 (epsilon = 2.2) has been performed using the calculated spectrum of Open(3), which appears to be the most populated in this solvent. A combined theoretical-experimental VCD spectroscopy approach was used to increase the spectroscopic sensitivity toward changes in the distribution of conformers upon change of solvent polarity. The VCD spectra confirm that Open(3) is by far the most stable conformation in CCl4 (epsilon = 2.2) and indicate that an excess Closed(2) conformer has to be expected in CD2Cl2 (epsilon = 8.9). The possible influence of this conformational behavior is discussed on the basis of available catalytic data and in relation to the enantioselective potential of PhOCD as a chiral modifier on supported metal catalysts.     

Conformer Pair Contributions to Optical Rotations in a Series of Chiral Linear Aliphatic Alcohols

The chain length effect of four chiral aliphatic alcohols,(S)-2-butanol,(S)-2-pentanol,(S)-2-hexanol and (S)-2-heptanol,on their specific optical rotations(OR)was studied experimentally and theoretically via quantum theory.Many conformations of each chiral alcohol exist as conformer pairs in solution.The OR sum from these pairs of conformers has much smaller contributions to OR values than that contributed by the most stable conformation. These four alcohols'OR values were also investigated using the matrix model,which employs each substituent's comprehensive mass,radii,electronegativity and symmetry number as the elements in the matrix.These are all particle properties.This matrix determinant is proportional to its OR values within a closely related structural series of chiral compounds.The experimental OR values and the matrix determinants of these four alcohols were compared with the predicted OR values obtained from quantum theory wave functions.The ORs predicted by the matrix method, which is based on particle function statistics,agreed with the results from quantum theory.The agreement between OR predictions by the matrix method and DFT calculations illustrates the wave-particle duality of polarized light that is operating in these predictions.     

Bicorannulenyl: stereochemistry of a C40H18 biaryl composed of two chiral bowls

The bicorannulenyl molecule is composed of two chiral bowls tethered by a single bond in a helical fashion. This simple combination of two chiral motifs gives rise to rich dynamic stereochemistry, where 12 conformers interconvert through bowl inversions and central bond rotation, and enantiomerizations occur via multistep processes. Interestingly, 8 out of 10 transition states are chiral, giving rise to mostly chiral enantiomerization pathways, where the molecule changes chirality without passing through an achiral conformation. However, analysis of the stereochemical landscape by DFT calculations and variable temperature NMR spectroscopy reveals that the energetically most favorable enantiomerization pathway passes through one of the two achiral transition states. Single-crystal X-ray diffraction corroborates the DFT results and provides information on packing modes of bicorannulenyl molecules in the solid state that have not been seen previously for other buckybowls.     

X-ray structure and circular dichroism of pure rotamers of bis[guanosine-5'-monophosphate(-1)](N,N,N',N'-tetramethylcyclohexyl-1,2-diamine)platinum(II) complexes that have R,R and S,S configurations at the asymmetric diamine

The use of a sterically hindered diamine ligand (Me(4)DACH) has allowed for the first time, the isolation and characterization, both in the solid state (X-ray crystallography) and in solution (circular dichroism), of pure DeltaHT rotamers of [Pt(Me(4)dach)(5'-GMP)(2)] (compounds 1 and 2 for R,R and S,S configurations of the Me(4)DACH ligand, respectively). Comparison of the CD spectra obtained for each rotamer, which differ only in the chirality of the Me(4)DACH ligand (R,R or S,S) or in the chirality of the HT conformation (Delta or Lambda), allowed us to conclude that, in the 200-350 nm range, the contributions to the overall CD spectrum that stem from diamine chirality and diamine-induced chirality of platinum d--d transitions or from sugar chirality are negligible relative to the exciton chiral coupling that occurs for pi-pi* transitions of the cis guanines. Accurate molecular structures of 1.10 D(2)O and 2.14 D(2)O (conventional crystallographic agreement indexes R(1) convergent to 2.07 % and 2.18 %, respectively) revealed that the crystallized rotamers have a DeltaHT conformation that is in agreement with all previously reported X-ray structures of [Pt(diamine)(nucleos(t)ide)(2)] complexes. This conformation allows the 5'-phosphate to be located in proximity to the Me(4)DACH ligand so that (P)O...HC(N) hydrogen-bond interactions exists in both complexes. For both structures, the canting of the guanine planes on the coordination plane is right-handed (R; canting angle (Phi) of 80.9 degrees and 73.2 degrees, respectively); this indicates that the canting direction is driven by the HT conformation chirality (Delta for both compounds) and not by the chirality of the carrier ligand (different for the two compounds). Density functional theory analysis of the conformational space as a function of Phi indicated a good agreement between the computed and experimental structures. The increase in energy for Phi values below 65 degrees and 55 degrees (for 1 and 2, respectively) is mainly due to the short intramolecular contacts between C(8)H and the cis N-Me groups on the same side of the platinum coordination plane.     

Development of versatile cis- and trans-dicarbon-substituted chiral cyclopropane units: synthesis of (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine

The cyclopropane ring can be used effectively in restricting the conformation of biologically active compounds to improve activity and also to investigate bioactive conformations. We designed (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes (1 and 2, respectively) and their enantiomers (ent-1 and ent-2) as conformationally restricted analogues of histamine. The four types of chiral cyclopropanes bearing two differentially functionalized carbon substituents in a cis or trans relationship on a cyclopropane ring, (1S,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (7) and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (8) and their enantiomers (ent-7 and ent-8), were developed as the key intermediates for synthesizing 1, 2, ent-1, and ent-2. The reaction between (R)-epichlorohydrin [(R)-12] and phenylsulfonylacetonitrile (13a) in the presence of NaOEt in EtOH followed by treatment with acid gave the chiral cyclopropane lactone 11a with 98% ee in 82% yield. Compound 11a was converted into both the cis- and trans-chiral cyclopropane units 7 and 8, respectively, via reductive desulfonylation with Mg/MeOH as the key step. The corresponding enantiomers, the cis-substituted ent-7 and the trans-substituted ent-8, were also prepared starting from (S)-epichlorohydrin [(S)-12]. The four conformationally restricted target histamine analogues 1, 2, ent-1, and ent-2 were successfully synthesized from 7, 8, ent-7, and ent-8, respectively. The chiral cyclopropane units 7, 8, ent-7, and ent-8 should be useful as versatile intermediates for synthesizing various compounds having an asymmetric cyclopropane structure.     

DFT study of vibrational circular dichroism spectra of D-lactic acid-water complexes

This paper presents a discussion of the interaction energies, conformations, vibrational absorption (VA, harmonic and anharmonic) and vibrational circular dichroism (VCD) spectra for conformers of monomeric chiral d(-)-lactic acid and their complexes with water at the DFT(B3LYP)/aug-cc-pVDZ and DFT(B3LYP)/aug-cc-pVTZ levels. A detailed analysis has been performed principally for the two most stable complexes with water, differing by lactic acid conformation. The VCD spectra were found to be sensitive to conformational changes of both free and complexed molecules, and to be especially useful for discriminating between different chiral forms of intermolecular hydrogen bonding complexes. In particular, we show that the VCD modes of an achiral water molecule after complex formation acquire significant rotational strengths whose signs change in line with the geometry of the complex. Using the theoretical prediction, we demonstrate that the VCD technique can be used as a powerful tool for structural investigation of intermolecular interactions of chiral molecules and can yield information complementary to data obtained through other molecular spectroscopy methods.     

Self-assembly and gelation behavior of tris(phenylisoxazolyl)benzenes

Low-molecular-mass organic gelators (LMOG), tris(phenylisoxazolyl)benzenes, were synthesized, and their self-assembling behavior was examined using (1)H NMR and UV-vis absorption spectroscopies. They turned into a gel in both nonpolar and highly polar solvents such as methylcyclohexane, ether, acetone, dimethylsulfoxide, etc. Field emission scanning electron microscopy (FESEM) observation of the xerogels of 1 and 3 possessing the saturated alkyl chains revealed that well-developed straight fibers were formed, whereas the unsaturated termini of the alkyl chains of 2 promoted the formation of both the right- and left-handed helical fibers. The self-association behavior of 1, 2, and 5 in solution were investigated using (1)H NMR and UV-vis spectroscopies. The flat aromatic compound 1 stacked in a columnar fashion along its C(3) axis via π-π stacking interactions. The assemblies were regulated by the peripheral alkyl substituents; the saturated alkyl groups facilitated the assemblies while terminal double bonds impeded the intermolecular association, and the branched substituents obviously interfered in the formation of the stacks, probably due to steric requirements. Theoretical calculations suggest that the three dipoles of the isoxazole groups adopt the circular array. The conformational search of the hexameric stacks of 4 using MacroModel V9.1 gave rise to two major conformers: one is nonhelical and the other is helical. Further detailed structural analysis of the assemblies of chiral 5 using circular dichroism (CD) measurements indicated that their assemblies adopt helical structures in solution. CD spectra and DFT calculations revealed that R-5 forms a left-handed supramolecular helicate. The coassembly of R- and S-5 displayed chiral amplification, since the chiral information from 5 was transferred to the supramolecular chirality of the helical assemblies of 1. A small amount of optically active 5 provided enough chiral stimulus to produce a remarkable chiral response and supramolecular helical structures of 1.     

Theoretical study of the structures and properties of cyclic nitramines: Tetranitrotetraazadecalin (TNAD) and its isomers

Density Functional Theory (DFT) was employed to study the geometries, electronic structures, infrared vibrational spectra, and thermodynamic properties of seven isomeric cyclic nitramines of C₆H₁₀N₈O₈ (i.e., TNAD and its six isomers) at the B3LYP/6‐31G* level of theory. The experimental results available for TNAD were used to determine the reliability of the DFT method for generating structural and IR spectroscopic values for these molecular systems. The relative stabilities of the conformers were evaluated from the energy differences of the structures. Detonation properties of various conformers were evaluated using the Kamlet‐Jacobs equations, and it was found that all the calculated results are comparable to the available experimental data. In addition, the calculated results demonstrate that all title compounds can be used as excellent propellant ingredients. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Circular dichroism and conformational dynamics of cephams and their carba and oxa analogues

The biological activity of bicyclic beta-lactam antibiotics depends strongly on the absolute configuration of the bridgehead carbon atom. Frelek and co-workers proposed an empirical helicity rule relating the configuration of the bridgehead carbon atom to the sign of the 220 nm band in the electronic circular dichroism (CD) spectrum of beta-lactams. Here we use synthetic organic chemistry, CD spectroscopy, and time-dependent density functional theory (TDDFT) to investigate the validity of this structure-property relationship for eight model compounds. For conformationally flexible beta-lactams, substantial thermal effects are found which must be included in calculations. To this end, we combine TDDFT calculations of CD with full quantum-mechanical Born-Oppenheimer molecular dynamics (MD) simulations for the first time. The CD spectra are sampled with ground-state density functional trajectories of up to 60 ps. The MD simulations show a surprisingly high sensitivity of the CD to the molecular conformation. On the other hand, the relation between CD and thermally averaged structural parameters is much less complex. While the helicity rule does not seem to hold for individual conformers, it is confirmed by the calculations for seven out of eight systems studied if thermally averaged CD spectra and structures are considered. Since thermal effects on CD can be larger than typical inherent inaccuracies of TDDFT, our results emphasize the need for a systematic treatment of conformational dynamics in CD calculations even for moderately flexible systems. Temperature-dependent CD measurements are very useful for this purpose. Our results also suggest that CD spectroscopy may be used as a sensitive probe of conformational dynamics if combined with electronic structure calculations.     

Synthesis and structural characterization of cis- and trans-fused 4a,5,6,7,8,8a-hexahydro-2H,4H-1,3-benzodithiines and their 2-methyl and 2,2-dimethyl derivatives

Both cis- and trans-fused 4a,5,6,7,8,8a-hexahydro-2H,4H-1,3-benzodithiine together with their 2-methyl and 2,2-dimethyl derivatives were prepared as racemates from the appropriate dithiols obtained via multistep syntheses. The products were characterized by (1)H and (13)C NMR, mass spectrometry, and for two of the cis-fused compounds by X-ray diffraction. (1)H,(1)H vicinal coupling constants indicated that all compounds attain chair-chair conformations as their predominant conformations. All three trans-fused isomers exist in totally biased chair-chair conformations and are essentially conformationally locked, whereas the cis-fused compounds are conformationally mobile and can potentially attain either the S-in or the S-out conformation. The interconversion of the conformers is fast on the NMR time-scale at ambient temperatures, but at 213 K 4ar,5,6,7,8,8ac-hexahydro-1,3-benzodithiine freezes out into a 83:17 mixture of the S-in and S-out forms, respectively. Both 2c-methyl-4ar,5,6,7,8,8ac-hexahydro-1,3-dithiine and the dimethyl derivative adopt almost exclusively the S-in conformer at ambient temperature whereas 2t-methyl-4ar,5,6,7,8,8ac-hexahydro-1,3-dithiine is a 5:1 mixture of the S-out and S-in conformers.     

Conformational study of (8alpha,8'beta)-bis(substituted phenyl)-lignano-9,9'-lactones by means of combined computational, database mining, NMR, and chemometric approaches

Beta-(3,4-Methylenedioxybenzyl)-gamma-butyrolactone (MDBL) and (-)-hinokinin (HK) were obtained by partial synthesis and characterized by 1H NMR and computational methods (conformational analysis, molecular modeling, structural data mining and chemometrics). Three conformers were detected for MDBL and nine were found for HK. The energy differences are around 1 and 2 kcal mol(-1) and rotation barriers are less than 3 and 5 kcal mol(-1) for MDBL and HK conformers, respectively. The geometries of these conformers, obtained from semiempirical PM3 and density functional theory (DFT) B3LYP 6-31G** calculations agree satisfactorily with 1H NMR data (vicinal proton-proton coupling constants) and structures retrieved from the Cambridge Structural Database (torsion angles). DFT combined with some variants of the Haasnoot-de Leeuuw-Altona equations gives the best predictions for the coupling constants. The molecular conformation of MDBL, of HK, and of related systems depends not only on intramolecular interactions but also on crystal packing forces and solvent-solute interactions, in particular hydrogen bonds and polar interactions. Hydration favors more stable HK conformers, which can be important for their behavior in chemical and biological systems.     

Chiral benzisoselenazolones: conformational analysis based on experimental and DFT calculated Se NMR

A series of new enantiomeric N-substituted benzisoselenazol-3(2H)-ones were prepared from 2-(chloroseleno)benzoyl chloride and 9-amino-deoxyquinine (both 9-native and 9-epi) as well as the other chiral primary amines. The ⁷⁷Se NMR parameters for the obtained benzisoselenazolones were measured and theoretically calculated at the DFT level of theory using B97-2 hybrid functional and cc-pVTZ basis set. The DFT ⁷⁷Se chemical shifts for the lowest energy conformers were in agreement with the experimental data, while the conformers of higher energy showed markedly worse fit. Interestingly, the preferred conformation for 2-(1-arylalkyl)-benzisoselenazolones is the gauche type (Se–N–C–H≈±180°), and it is in agreement with those observed in crystals (X-ray). The calculation predicts a much higher sensitivity for the ⁷⁷Se chemical shift of the conformation than for the corresponding ¹³C data. In the ⁷⁷Se NMR spectra of chiral benzisoselenazolones with added racemic or l-N-Boc-phenylglycine, chiral discrimination could not be observed mostly due to signal broadening. In the ¹H NMR spectra, the benzisoselenazole derived from epi-9-amino-deoxyquinine induced splittings of the amino acid signals, thus allowing for discrimination of the enantiomers.     

Assignment of absolute configuration of a chiral phenyl-substituted dihydrofuroangelicin

A phenyl-substituted chiral dihydrofuroangelicin, 4-methyl-8-(2-E-phenylethenyl)-8,9-dihydro-2H-furo[2,3-h]- 1-benzopyran-2-one, synthesized in racemic form, has been resolved by HPLC chiral separation, and its absolute configuration determined by the non-empirical exciton chirality method. The solution conformation has been investigated through NMR and molecular modeling methods: two minima found by molecular mechanics and DFT methods are in keeping with observed 1H-1H 3J coupling constants and NOE effects. The experimental CD spectrum for the second eluted enantiomer shows a positive couplet between 230 and 350 nm (amplitude A = + 15.7); by application of the exciton chirality method, the absolute configuration of this enantiomer at C8 is determined as (S). The experimental spectrum is in very good agreement with the one evaluated by means of DeVoe coupled-oscillator calculations, using the DFT calculated geometries.     

药效团检索设计新的HIV-1蛋白酶抑制剂

通过对自建的未开发化合物三维结构库进行药效团检索,得到了4个对HIV-1蛋白酶抑制活化的化合物,通过构象分析发现包含药效团的构象处于优势构象,而且4个结构都含有带两个邻位羟基的苯环和一个间位羰基的药效团以及公共子结构。通过计算发现它们的疏水参数都很小。在考虑满足包含药效团的结构特征和有适中的疏水参数两个因素的前提下,设计出了新的具有潜在抑制HIV-1蛋白酶活性的化合物。它们的结构都比检索得到的四个化合物更为简单,因此易于合成。