JP4941869B2 - Conformational analysis apparatus and analysis method - Google Patents

Description

  The present invention relates to an apparatus and method for simply and more precisely analyzing the conformation of a drug active species related to drug efficacy and the like.

  As the progress of post-genome research, various protein structures are revealed. For example, taxol (paclitaxel), which functions as an anticancer agent, inhibits depolymerization by stabilizing the binding to a protein called tubulin that forms microtubules. As a result, it has been found to inhibit cancer cell division. Furthermore, under the environment where the drug functions, since the drug takes a liquid phase state, for example, taxol can take various forms, and the structure of the active species is interesting from the viewpoint of the structure-activity relationship. These various forms are referred to as conformations. Concerning taxol, conformations of various active species have been proposed and have been discussed (Non-patent Document 1). However, how to describe the conformation of the active species due to the limitations of the spatial resolution of existing devices, the limitations of the NMR time scale unique to nuclear magnetic resonance (NMR) devices, and the accuracy of molecular force field calculations. There is interest in For example, currently, notation such as T-Taxol and PTX-NY is used for taxol, but it is impossible to compare the conformation itself from such notation itself.

  For the genome, it is possible to perform large-scale computer processing by using the common G, C, T, and A simplified symbols, and it has made tremendous progress.

  The present inventors have found that the infrared circular dichroism (VCD) band of substances having chirality such as biomolecules is extremely sensitive to conformation (Non-patent Documents 2 and 3). Have already made proposals regarding a new structure analysis method utilizing VCD spectroscopy (Patent Documents 1 and 2). Among them, a proposal has been made to describe the conformation using a simplified symbol, but there is a problem that it cannot be distinguished when there is a subtle difference in structure.

The activity of a drug is thought to depend on physical properties that are due to the conformation of the molecule and properties that are related to metabolism. The conformation structure of the active species has been attracting attention from the viewpoint of structure-activity relationship for the design of new drugs, but the conformation structure of the molecule can be simplified by the conventional method of expressing the molecular conformation using the orthogonal coordinate system or ZMATRIX. It was not possible to write it down, and a simple notation such as T-Taxol or PTX-NY unique to each was required. However, since the conformations can not be easily compared even with such a simple notation, it is possible to perform large-scale computer processing and a notation for easily comparing the conformations. An analysis technique using this was required.
AA Alcaraz et al., J. Med. Chem., 2006, 49, 2478 H. Izumi et al., J. Am. Chem. Soc., 2004, 126, 194 H. Izumi et al., J. Org. Chem., 2007, 72, 277 Japanese Patent Laying-Open No. 2005-91050 JP 2005-91164 A

  The present invention has been made in view of such a state of the art, and can be distinguished even when there are subtle structural differences in conformation, and any molecule can be handled in a unified manner. It is an object of the present invention to provide a conformation analysis device and an analysis method capable of performing large-scale computer processing.

  In order to solve the above-described problems, first, the present invention provides a processing unit that receives an input of a chemical structural formula of a compound to be analyzed, and the processing unit receives each chemical bond based on the received chemical structural formula. The structure with a predetermined code representing the dihedral angle attached to the part, and the conformation can be uniquely determined by one conformation notation, extracted the notation of the encoded conformation of interest and extracted The encoded conformation notation is stored in a storage unit, and the processing unit creates a molecular model based on the extracted encoded conformation notation, and the processing unit optimizes the structure of the created molecular model and The frequency calculation is performed, the optimized structure and the physical property value of the optimized structure are obtained, and the processing unit takes out the encoded conformational notation from the storage unit, and analyzes the homology based on the extracted conformational notation. Proposed conformational analysis method To.

  Second, in the above method, the compound to be analyzed is an optically active molecule, and by comparing the actually measured infrared circular dichroism spectrum with the predicted spectrum obtained from the candidate conformation, There is provided a conformational analysis method characterized by verifying the conformational structure of an optically active molecule.

  Thirdly, in the above method, there is provided a conformational analysis method characterized in that a rule based on the IUPAC notation is adopted as a method of expressing a dihedral angle.

Further, according to the present invention, fourthly, a means for receiving an input of a chemical structural formula of a compound to be analyzed, and a predetermined code representing a dihedral angle at each chemical binding site based on the chemical structural formula received. In addition, for the structure in which the conformation can be uniquely determined by one conformation notation, the notation of the noticed encoded conformation is extracted and the extracted encoded conformation notation is stored in the storage means , Means for creating a molecular model based on the notation of the extracted encoded conformation, means for optimizing the structure of the created molecular model and calculating the frequency, and determining the optimized structure and the physical property value of the optimized structure, And a conformation analysis device comprising means for extracting the encoded conformation notation from the storage means and analyzing homology based thereon.
Fifth, the apparatus further includes means for comparing the measured infrared circular dichroism spectrum with the predicted spectrum obtained from the candidate conformation when the compound to be analyzed is an optically active molecule. And a conformation analysis apparatus characterized by verifying the conformation structure of an optically active molecule in a liquid phase.

  Sixthly, in the above apparatus, there is provided a conformational analysis apparatus characterized in that a rule conforming to the IUPAC notation is adopted as a method of expressing a dihedral angle.

  According to the present invention, since the conformation is analyzed using a method of encoding the position and dihedral angle of a chemical bond and expressing the conformation of the molecule, there is a subtle structural difference in the conformation. Can be distinguished even if there is, it is possible to handle any molecule in a unified manner, enabling large-scale computer processing.

  Further, according to the present invention, by adopting a rule based on the IUPAC notation, the classification can be made finer and the conformation can be analyzed with higher accuracy.

  Further, according to the present invention, it has been impossible to compare the conformations of the active species with the conventionally used notation itself such as T-Taxol and PTX-NY. The notation used allows easy comparison of the conformational differences of each active species, facilitates the creation of a database for each molecular block, and uses infrared circular dichroism data in combination. By doing so, a conformation structure with a large abundance ratio in a liquid phase state can be taken out.

  Therefore, the present invention can be used for, for example, the design of new drugs that are being promoted with reference to the conformation of the active species of taxol. The development of application such as drug discovery by pharmacological proteomics is fully expected.

It is a system block diagram of the conformation analysis apparatus of this invention. It is a flowchart of the analysis process which concerns on this invention. It is a figure which shows the classification | category of eight types of conformations by the IUPAC notation. It is a figure which shows the molecular model of the conformation represented with tail + 4322324. It is a figure which shows the chemical structural formula of a paclitaxel and a paclitaxel tail methyl ester. It is a figure which shows the molecular model of the conformation represented by pipe4 (phim3). It is a figure which shows the molecular model of the conformation represented by pipe4 (phim3) pipe4 (phim3) BB. It is a figure which shows the molecular model of the conformation represented by tail-4633 + 14. It is a figure which shows the molecular model of the conformation represented by PS2211Etsu13111. It is a figure which shows the measurement and prediction average infrared circular dichroism spectrum of (+)-malathion (IV). It is a figure which shows the molecular model of the conformation represented by bacc233323. It is a figure which shows the measurement and prediction average infrared circular dichroism spectrum of baccatin III (V) with an infrared spectrum.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Display part 2 Input part 3 Processing part 4 Main memory part 5 Output part 6 External interface (I / O) part 7 Database 8 Bus

  Hereinafter, the present invention will be described in detail based on preferred embodiments.

  FIG. 1 is a system configuration diagram of the conformational analysis apparatus of the present invention. This conformational analysis apparatus includes a display unit 1, an input unit 2, a processing unit 3, a main storage unit 4, an output unit 5, an external interface (I / O) unit 6, and a database 7. These units are connected by a bus 8. Has been. Such a conformational analysis apparatus can be constructed by, for example, a personal computer incorporating a program for performing a conformational analysis.

  The display unit 1 includes a CRT, a liquid crystal display, and the like, and displays a screen for conformational analysis. The input unit 2 includes various input means such as a keyboard and is used for inputting data and information required by the user. The processing unit 3 can be composed of a CPU, and performs various controls and calculations for conformational analysis. The main storage unit 4 stores a program for conformational analysis. The output unit 5 includes a printer or the like, and outputs a processing result or the like to the user. An external interface (I / O) unit 6 connects to other terminal devices via a LAN, the Internet, or the like. The database 7 stores various data for conformational analysis in a rewritable manner.

  The conformational analysis apparatus of the present invention uses an encoded notation that incorporates rules conforming to the IUPAC notation. For this reason, as long as the compound used as the analysis object of this invention is an organic compound, it may have either a chain structure or a cyclic structure in a part of structure. Furthermore, it may be substituted with a functional group such as an ester group, a carbonyl group, a hydroxyl group, a phenyl group, an alkene, a halogen, a phosphorus atom, or a sulfur atom. Further, it may have a structure which is not a covalent bond, for example, a hydrogen bond or a coordinate bond. However, when a conformational structure having a large abundance ratio in the liquid phase is extracted by combining infrared circular dichroism data, the compound to be analyzed is limited to an optically active molecule.

  As such an organic compound, the following compounds can be illustrated, for example.

  Thalidomide, thalidomide dimer, 5'-hydroxythalidomide, phthalimide, dioxopiperidine, paclitaxel, paclitaxel tail, paclitaxel tail methyl ester, baccatin III, benzamide, malathion, diethylsuccinate, 2-mercaptodiethylsuccinate, 2-butanol 2-pentanol, 2-hexanol, 2-heptanol, 2-octanol, 2-nonanol, 2-decanol, 2-methyl-1-butanol, 3-methyl-1-pentanol, 4-methyl-1-hexanol 5-methyl-1-heptanol, 6-methyl-1-octanol, cis-permethrin, cis-3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylic acid benzyl ester, cis-3- (2,2-dichlorovinyl) -2,2-dimethylcyclopropanecarboxylic acid methyl ester, 3-phenoxybenzyl alcohol , Cholesterol acetate, cholesterol propionate, n-butyric acid cholesterol ester, cholesterol n-valerate, cholesterol n-hexanoate, cholesterol n-heptanoate, cholesterol n-caprylate, cholesterol pelargonate, cholesterol n-caprate, cholesterol laurate , Cholesterol myristate, cholesterol palmitate, cholesterol, β-cholestanol, cholesteryl chloride, cholesteryl bromide, cholesterol methyl carbonate, cholesterol ethyl carbonate, cholesterol-n-butyl carbonate, cholesterol-n-amyl carbonate, cholesterol- n-hexyl carbonate, cholesterol-n-heptyl carbonate, cholesterol Roll-n-nonyl carbonate, cholesterol oleyl carbonate.

  The outline of the conformational analysis by the conformational analysis apparatus of this embodiment will be described. First, the processing unit 3 accepts the input of the chemical structural formula of the analysis target compound. Next, the processing unit 3 attaches a predetermined code representing a dihedral angle to each chemical bonding site based on the chemical structural formula that has received the input, and the conformation is uniquely defined by one conformational notation. For the structure that can be determined, the notation of the encoded conformation of interest is extracted, and the extracted encoded conformation notation is stored in the database 7. Next, the processing unit 3 creates a molecular model based on the extracted encoded conformation notation, performs structural optimization and frequency calculation of the created molecular model, and creates an optimized structure and its optimized structure. Obtain physical properties. And the process part 3 takes out the said encoding conformation description from the database 7, and analyzes a homology based on it.

  In more detail with reference to the flowchart of FIG. 2, in the present invention, conformation notation is first defined based on the chemical structural formula by attaching a symbol representing a dihedral angle to each chemical bonding site (step). S1-S3). In this case, for example, the compound name and the chemical structural formula are associated with each other in advance and the information is stored in the database 7 so that when the user inputs the compound name from the input unit 2, it can be converted into the corresponding chemical structural formula. May be.

  Next, for structures that can uniquely determine the conformation with a single conformation notation, such as when having a ring structure, omit the unnecessary notation, leaving the notation of the chemical bond of interest, and unambiguous conformation The notation shown is defined (steps S4 and S5). Based on this definition, it uses for the conformational analysis using the notation which extracted only the code | symbol. From the viewpoint of creating a database, when it is simpler to separate the compounds into blocks, a combination of blocks and codes may be used.

  Here, as a method of attaching a sign representing a dihedral angle, a rule based on the IUPAC notation is adopted from the viewpoint of standardization. That is, in the IUPAC notation, it is defined that the conformation is expressed based on two twist angles formed by the ligands bonded to the respective ends of the chemical bond of interest. In addition, the ligand priority rules are as follows: (1) When all the ligands are different, the highest priority is given by the ranking rule determined by the R / S display. (2) When only one is different from the others, it is the same regardless of the ranking. (3) When all are the same, it is determined that the twist angle is the smallest. Furthermore, it is stipulated to classify into 8 classes using expressions of +/-, syn / anti, and periplanar / clinal. A chart of these eight types of classification is shown in FIG. In the present invention, these rules are taken in and conformational analysis is performed.

  Furthermore, in the present invention, for example, four classes of ap, + sc, -sc, and sp are mainly used, and when detailed description is necessary, these are + ac, -ac, + ap. , -Ap, + sp, -sp are used, and a total of 10 classes are used. Specifically, ap = 1, + sc = 2, −sc = 3, sp = 4, + ac = 5, −ac = 6, + ap = 7, −ap = 8, + sp = +, −sp Conformation is expressed by adding the sign of −. For example, in paclitaxel tail methyl ester, the chemical structural formula is represented as (PhCONH) PhCHOHCHCO (OMe), and the conformation is (Ph + CO4NH) 3Ph2CH2OH3CH2CO4 (OMe) and the conformation is expressed as tail + 4322324. To do. The conformational molecular model represented by tail + 4322324 is shown in FIG. Here, Ph represents a phenyl group, and Me represents a methyl group (hereinafter the same).

  In paclitaxel, the conformation defined as baccOH2 (PhCOO) 3 (MeCOO) 3OH1 (MeCOO) 5 (tail + 4322324) 3 may be expressed as bacc233153 (tail + 4322324). The chemical structural formulas of paclitaxel and paclitaxel tail methyl ester are shown in FIG.

  In the conformation analysis apparatus of this embodiment, the analysis is performed in association with the conformation notation. That is, a molecular model is created based on the conformational notation (step S6), the structure is optimized and the frequency is calculated (step S7), and the energy value and physical property value of the optimized structure are calculated. Obtain (step S8). Further, homology is analyzed using the conformational notation (step S9), and conformational information related to physical properties and activity is analyzed (step S10). Here, there are no particular limitations on the method of molecular model structure optimization and frequency calculation, but molecular orbital calculation by density functional method using B3LYP functional is preferably used.

  Furthermore, in the present invention, when the target compound is an optically active molecule, the liquid phase is confirmed by confirming the coincidence between the actually measured infrared circular dichroism spectrum and the predicted spectrum obtained from the candidate conformation. The conformational structure of the optically active molecule in the inside can be verified (steps S11 to S13).

  For example, the method described in Patent Document 2 may be used to search for conformational candidates. There is no particular limitation on the method of creating a predicted spectrum from the candidate conformation, but preferably, after obtaining the Gibbs free energy from the frequency calculation by the density functional method using the B3LYP functional, it is converted into a Boltzmann population, What is necessary is just to obtain | require an average spectrum by adding the thing which multiplied the coefficient of the Boltzmann population to the prediction spectrum of each conformation.

  Note that the conformation coding process, the molecular model structure optimization, and the physical property value extraction process may be mixed. In addition, for example, the conformational structure obtained from different measurement analyzes such as the conformational structure of an organic molecule incorporated into a protein may be analyzed for homology using the conformational notation. Absent.

  There is no restriction on the apparatus used for the infrared and infrared circular dichroism measurement used in the present invention, and for example, Chiralir manufactured by Bomem / BioTools can be used as the infrared spectrum apparatus and the infrared circular dichroism spectrum apparatus. .

The solvent used for infrared circular dichroism measurement can be either a hydrophobic solvent or a hydrophilic solvent, preferably carbon tetrachloride, deuterated chloroform, deuterated methylene chloride, deuterated dimethyl sulfoxide, water, etc. Is done. When the target compound is a liquid, it can be measured with neat.
As the window plate of the sample cell, any material can be used as long as it transmits infrared rays. However, a NaCl plate and a BaF ₂ plate are preferable.

  There is no particular limitation on the integration time of the infrared circular dichroism measurement, but 20 minutes to 4 hours are desirable in order to obtain sufficient S / N.

  There is no particular limitation on the approximation method used for fitting the infrared circular dichroic band, but Lorentz function approximation or Gaussian function approximation is preferably used.

Next, the present invention will be described in more detail with reference to examples.
Example 1
The conformational notation was defined by attaching a symbol representing a dihedral angle to each chemical binding site of thalidomide represented by the following chemical structural formula (I). Next, the notation of the unnecessary chemical notation was omitted, leaving the notation of the chemical bond of interest, and the notation indicating the conformation was defined. Based on this definition, the notation from which only the code was extracted was determined. Next, for the molecular model based on the encoded conformational notation, the structure was optimized by the density functional method using B3LYP functional and the frequency was calculated, and the energy value of the optimized structure was obtained. The homology was analyzed using the encoded conformation notation, and the conformation structure pipe4 (phim3) having a large abundance ratio in the liquid phase was extracted. Table 1 shows the results of the analysis of the encoded conformation notation and homology. A molecular model of the conformation represented by pipe4 (phim3) is shown in FIG.

Example 2
The conformational notation was defined by attaching a symbol representing a dihedral angle to each chemical binding site of a series of thalidomide dimers represented by the following chemical structural formula (II). Next, the notation of the unnecessary chemical notation was omitted, leaving the notation of the chemical bond of interest, and the notation indicating the conformation was defined. Based on this definition, the notation from which only the code was extracted was determined. Next, for the molecular model based on the encoded conformational notation, the structure was optimized by the density functional method using B3LYP functional and the frequency was calculated, and the energy value of the optimized structure was obtained. The homology was analyzed using the encoded conformation notation, and the conformation structure pipe4 (phim3) pipe4 (phim3) BB having a large abundance ratio in the liquid phase was extracted. Table 2 shows the results of the analysis of the encoded conformation notation and homology. A conformational molecular model represented by pipe4 (phim3) pipe4 (phim3) BB is shown in FIG.

Example 3
The conformational notation was defined by attaching a sign representing a dihedral angle to each chemical binding site of paclitaxel tail methyl ester represented by the following chemical structural formula (III). Next, the notation of the unnecessary chemical notation was omitted, leaving the notation of the chemical bond of interest, and the notation indicating the conformation was defined. Based on this definition, the notation from which only the code was extracted was determined. Next, for the molecular model based on the encoded conformational notation, the structure was optimized by the density functional method using B3LYP functional and the frequency was calculated, and the energy value of the optimized structure was obtained. The homology was analyzed using the encoded conformation notation, and a conformation structure tail-4633 + 14 having a large abundance ratio was extracted. Table 3 shows the results of the encoded conformation notation and homology analysis. A conformational molecular model represented by tail-4633 + 14 is shown in FIG.

Example 4
The conformation notation was defined by attaching a sign representing a dihedral angle to each chemical bonding site of (+)-malathion represented by the following chemical structural formula (IV). Next, the notation of the unnecessary chemical notation was omitted, leaving the notation of the chemical bond of interest, and the notation indicating the conformation was defined. Based on this definition, the notation from which only the code was extracted was determined. Next, for the molecular model based on the encoded conformational notation, the structure is optimized and the frequency is calculated by the density functional method using B3LYP functional. The value of the optical rotation intensity was obtained for each vibration mode. The homology was analyzed using the encoded conformation notation, and the conformation structure PS2211Etsu13111 having a large abundance ratio was extracted. Table 4 shows the results of the analysis of the encoded conformation notation and homology. A conformational molecular model represented by PS2211Etsu13111 is shown in FIG.

  Next, a predicted spectrum of each conformation was created using the value of optical rotation intensity for each vibration mode in the infrared region. The Gibbs free energy value of the optimized structure was converted to Boltzmann population, and then the average predicted spectrum was created by adding the predicted spectrum of each conformation multiplied by the coefficient of Boltzmann population.

On the other hand, (+)-malathion (IV) was dissolved in carbon tetrachloride to a concentration of 0.11 M, then placed in a BaF ₂ window sample cell, integrated for 4 hours, and infrared circular dichroism spectrum (VCD) ) And infrared absorption spectra (IR) were collected. When the measured infrared circular dichroism spectrum was compared with the average predicted spectrum, a very good agreement was confirmed. This confirms that the absolute configuration of (+)-malathion is (R) -malathion and that the conformation represented by PS2211Etsu13111 is included in the conformation having a large abundance ratio in carbon tetrachloride. It was. A chart comparing the measured infrared circular dichroism spectrum and the average predicted spectrum is shown in FIG.

Example 5
The conformational notation was defined by attaching a sign representing a dihedral angle to each chemical binding site of baccatin III forming the skeleton of paclitaxel represented by the following chemical structural formula (V). Next, the notation of the unnecessary chemical notation was omitted, leaving the notation of the chemical bond of interest, and the notation indicating the conformation was defined. Based on this definition, the notation from which only the code was extracted was determined. Next, for the molecular model based on the encoded conformational notation, the structure is optimized and the frequency is calculated by the density functional method using B3LYP functional. The value of the optical rotation intensity was obtained for each vibration mode. The homology was analyzed using the encoded conformation notation, and the conformation structure bacc233323 having a large abundance ratio was extracted. Table 5 shows the results of the encoded conformation notation and homology analysis. A conformational molecular model represented by bacc233323 is shown in FIG.

  Next, a predicted spectrum of each conformation was created using the value of optical rotation intensity for each vibration mode in the infrared region. The Gibbs free energy value of the optimized structure was converted to Boltzmann population, and then the average predicted spectrum was created by adding the predicted spectrum of each conformation multiplied by the coefficient of Boltzmann population.

On the other hand, baccatin III (V) was dissolved in deuterated chloroform to a concentration of 0.029 M, then placed in a BaF ₂ window plate sample cell, integrated for 4 hours, infrared circular dichroism spectrum (VCD) and infrared Absorption spectra (IR) were collected. When the measured infrared circular dichroism spectrum was compared with the average predicted spectrum, a very good agreement was confirmed. From this, it was verified that the conformation represented by bacc233323 having an intramolecular hydrogen bond was included in the conformation having a large abundance ratio in deuterated chloroform. A chart comparing the measured infrared circular dichroism spectrum and the average predicted spectrum is shown in FIG. 12 together with the infrared spectrum.

  Furthermore, using the conformational conformation notation, the homology of the structure with paclitaxel bound to a protein called β-tubulin constituting the microtubule was verified. As a result, structural similarity with the unstable conformation represented by bacc233253 was found in the free solution state. This suggests that the substituents involved in intramolecular hydrogen bonding act like a switch on-off and play an important role in paclitaxel metabolism.

Industrial applicability

  The conformational analysis technology according to the present invention encodes the position and dihedral angle of a chemical bond in conformation instead of the conventional method of expressing the molecular conformation by the orthogonal coordinate system or ZMATRIX. Therefore, the conformation of the active species of taxol can be easily analyzed, for example, by conformation of the active species of taxol. It can be used for the design of new drugs that are being promoted for reference, and the development of applications such as the assessment of the effects of harmful substances on the human body and the discovery of drugs by pharmacological proteomics using structure-activity relationships is fully expected. It is what is done.

Claims (4)

The processing unit accepts the input of the chemical structure of the compound to be analyzed,
A conformation analysis method, wherein the processing unit performs a process including the following steps (1) to (8) on each molecular model created based on a chemical structural formula;
(1) The chemical structural formula that received the input is divided into fragment blocks, and the highest priority substitution is performed according to the IUPAC nomenclature ligand priority rules at each chemical binding site according to the position number order determined by the IUPAC nomenclature. Select a group or atom, determine the dihedral angle, and classify the dihedral angle based on the eight classes defined in the IUPAC nomenclature and 1 to 8 and + A step of attaching any sign of-
(2) Upon denoted the conformation of the fragment blocks, be omitted representation of a portion of the chemical bonds about the structure can be determined uniquely, the corresponding chemical bonds of interest of the conformational notation A process of notifying unnecessary signs and adding a sign or using a notation combining a sign of a block and the sign for accurately indicating only the position of a dihedral angle,
(3) By using the conformation notation defined by the above steps (1) to (2) (hereinafter referred to as encoded conformation notation), each molecular model corresponding to a different conformation is created, and the conformation A process for confirming that all the seats can be uniquely determined;
(4) extracting the encoded conformational notation corresponding to each molecular model, and storing the extracted encoded conformational notation corresponding to each molecular model in the database unit;
(5) Subsequently, the processing unit extracts each molecular model from the database unit based on the encoded conformation notation of each molecular model corresponding to the conformation of interest, and the structure of each molecular model perform optimization and frequency calculation, an object of value of the optimization structure determined, the physical properties comprising the steps is stored in the database unit to correspond to each molecule model and structure optimization results stereoscopic For the molecular model in which the conformation has changed, a new encoded conformational notation by the steps (1) to (3) is newly extracted, and the extracted encoded conformational notation is used as the molecular model. Storing the data in the database unit in correspondence with the physical property value in the database unit in correspondence with the molecular model,
(6) Further, an object of value actually measured for the analyzed compounds, processes to be stored in so as to correspond to those to which the physical properties are associated database portion of the molecular model corresponding to the analysis target compound,
(7) Next, in the processing unit, the encoded conformational notation corresponding to a plurality of molecular models for the analysis target compound is extracted from the database unit and stored in the step (5) or (6). and, corresponding to each of the molecular model, taking out any one or more of the physical properties of the optimized object values used structures, and that by the measured object property value step,
(8) Next, in the processing unit, for each molecular model corresponding to a different conformation of interest of the compound to be analyzed, analysis of homology is performed by associating the encoded conformation notation with the physical property values. Process.   In the steps (5) to (8) for analyzing the homology by associating the encoded conformation notation and the physical property values, the analysis target compound is an optically active molecule, and the measured infrared circular dichroism By comparing the predicted spectrum obtained from the candidate conformation extracted by analyzing the homology by associating the spectrum, the encoded conformation notation and the energy value, the optical in the liquid phase The conformational analysis method according to claim 1, wherein the conformational structure of the active molecule is verified. A processing unit for receiving an input of a chemical structural formula of a compound to be analyzed, and a database unit;
A conformational analysis apparatus, wherein the processing unit performs processing including the following steps (1) to (8) on each molecular model created based on a chemical structural formula:
(1) The chemical structural formula that received the input is divided into fragment blocks, and the highest priority substitution is performed according to the IUPAC nomenclature ligand priority rules at each chemical binding site according to the position number order determined by the IUPAC nomenclature. Select a group or atom, determine the dihedral angle, and classify the dihedral angle based on the eight classes defined in the IUPAC nomenclature and 1 to 8 and + A step of attaching any sign of-
(2) Upon denoted the conformation of the fragment blocks, be omitted representation of a portion of the chemical bonds about the structure can be determined uniquely, the corresponding chemical bonds of interest of the conformational notation A process of notifying unnecessary signs and adding a sign or using a notation combining a sign of a block and the sign for accurately indicating only the position of a dihedral angle,
(3) By using the conformation notation defined by the above steps (1) to (2) (hereinafter referred to as encoded conformation notation), each molecular model corresponding to a different conformation is created, and the conformation A process for confirming that all the seats can be uniquely determined;
(4) extracting the encoded conformational notation corresponding to each molecular model, and storing the extracted encoded conformational notation corresponding to each molecular model in the database unit;
(5) Subsequently, the processing unit extracts each molecular model from the database unit based on the encoded conformation notation of each molecular model corresponding to the conformation of interest, and the structure of each molecular model perform optimization and frequency calculation, an object of value of the optimization structure determined, the physical properties comprising the steps is stored in the database unit to correspond to each molecule model and structure optimization results stereoscopic For the molecular model in which the conformation has changed, a new encoded conformational notation by the steps (1) to (3) is newly extracted, and the extracted encoded conformational notation is used as the molecular model. Storing the data in the database unit in correspondence with the physical property value in the database unit in correspondence with the molecular model,
(6) Further, an object of value actually measured for the analyzed compounds, processes to be stored in so as to correspond to those to which the physical properties are associated database portion of the molecular model corresponding to the analysis target compound,
(7) Next, in the processing unit, the encoded conformational notation corresponding to a plurality of molecular models for the analysis target compound is extracted from the database unit and stored in the step (5) or (6). and, corresponding to each of the molecular model, taking out any one or more of the physical properties of the optimized object values used structures, and that by the measured object property value step,
(8) Next, in the processing unit, for each molecular model corresponding to a different conformation of interest of the compound to be analyzed, analysis of homology is performed by associating the encoded conformation notation with the physical property values. Process.   In the steps (5) to (8) for analyzing the homology by associating the encoded conformation notation and the physical property values, the analysis target compound is an optically active molecule, and the measured infrared circular dichroism By comparing the predicted spectrum obtained from the candidate conformation extracted by analyzing the homology by associating the spectrum, the encoded conformation notation and the energy value, the optical in the liquid phase The conformation analysis apparatus according to claim 3, wherein the conformation structure of the active molecule is verified.