Light has been recognized as one of the most important external factors in drug instability and the knowledge of photo-reactivity is essential in the overall profile of a drug. The drug photo-chemistry helps in the design of more photo-stable drugs as well as in the development of photo-protective systems. During the phases of drug design, investigation and prediction of the required properties of new molecules is very important, but for this aim a mathematical model is necessary. Quantitative Structure Property Relationships (QSPR) techniques help to establish a mathematical correlation between the molecular structure and chemical or chemical-physics properties of a series of compounds1. The derived relationships can be used to find the parameters affecting a specific property of the molecules or predict the behaviour of other molecules of the series2-3. A number of works about the application of QSPR analysis to photodegradation studies is present in Literature. A lot of descriptors that can clearly describe molecular properties have successfully been used to develop QSPR models to estimate photodegradation half-lives of persistent organic pollutants and to study the photolysis mechanism4. In our laboratory, we are trying to correlate the oxidation rate of a series of 1,4-dihydropyridines with their chemical structure by means of QSPR modeling. After that the defined model will be used to design new analogous structures with a potential higher stability to light. The effect of the different chemical substituents on both benzene and pyridinic rings has been evaluated in terms of hydrophobic, electronic and steric descriptors. The photodegradation processes have been carried out according to the “Guide for the Photostability Testing of New Drug Substances and Products” recommended by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH Harmonized Tripartite Guideline, 1996)5. QSPR model development is performed by means of multivariate regression methods, because of their ability in computing a high number of variables. Principal component regression (PCR) and partial least squares (PLS) regression are the mostly used modeling methods. A large set of descriptors has been tested, computing them in several PLS calibrations. The mean standard error of prediction (mSEP) has been adopted as a discriminating criterion. Molecular volume (MV) and Hydrophobic constant of Hansch-Fujita (π) have been selected as descriptors of substituents whereas Topological surface area (PSA), H bond donors (HDon) and H bond acceptors (HAcc) have been chosen as global descriptors. These descriptors have furnished the most useful information to define a well-fitted multivariate model. The work in progress is based on the application of the built model to plan the design of new 1,4-dihydropyridine molecules characterized by a high light stability. 1. A. Toropov, K. Nesmerak, I. Raska, K. Waisser, K. Palat. Comput. Biol. Chem. 30 (2006) 434–437 2. I. Raska, A. Toropovc. Eur. J. Med. Chem. 41 (2006) 1271–1278 3. P. Thanikaivelan, V. Subramanian, R.J. Raghava, U. Balachandran. Chem. Phys. Lett. 59 (2000) 323-327 4. J. Niu, L. Wang, Z. Yang. Ecotoxicol. Envir. Safety 66 (2007) 272–277 5. ICH Harmonized Tripartite Guideline. Photostability Testing of New Drug Substance and Products. Federal Register, 1996, 62, 27115.
The role of the photodegradation studies in drug design
DE LUCA M;IOELE, Giuseppina;RAGNO, Gaetano
2009-01-01
Abstract
Light has been recognized as one of the most important external factors in drug instability and the knowledge of photo-reactivity is essential in the overall profile of a drug. The drug photo-chemistry helps in the design of more photo-stable drugs as well as in the development of photo-protective systems. During the phases of drug design, investigation and prediction of the required properties of new molecules is very important, but for this aim a mathematical model is necessary. Quantitative Structure Property Relationships (QSPR) techniques help to establish a mathematical correlation between the molecular structure and chemical or chemical-physics properties of a series of compounds1. The derived relationships can be used to find the parameters affecting a specific property of the molecules or predict the behaviour of other molecules of the series2-3. A number of works about the application of QSPR analysis to photodegradation studies is present in Literature. A lot of descriptors that can clearly describe molecular properties have successfully been used to develop QSPR models to estimate photodegradation half-lives of persistent organic pollutants and to study the photolysis mechanism4. In our laboratory, we are trying to correlate the oxidation rate of a series of 1,4-dihydropyridines with their chemical structure by means of QSPR modeling. After that the defined model will be used to design new analogous structures with a potential higher stability to light. The effect of the different chemical substituents on both benzene and pyridinic rings has been evaluated in terms of hydrophobic, electronic and steric descriptors. The photodegradation processes have been carried out according to the “Guide for the Photostability Testing of New Drug Substances and Products” recommended by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH Harmonized Tripartite Guideline, 1996)5. QSPR model development is performed by means of multivariate regression methods, because of their ability in computing a high number of variables. Principal component regression (PCR) and partial least squares (PLS) regression are the mostly used modeling methods. A large set of descriptors has been tested, computing them in several PLS calibrations. The mean standard error of prediction (mSEP) has been adopted as a discriminating criterion. Molecular volume (MV) and Hydrophobic constant of Hansch-Fujita (π) have been selected as descriptors of substituents whereas Topological surface area (PSA), H bond donors (HDon) and H bond acceptors (HAcc) have been chosen as global descriptors. These descriptors have furnished the most useful information to define a well-fitted multivariate model. The work in progress is based on the application of the built model to plan the design of new 1,4-dihydropyridine molecules characterized by a high light stability. 1. A. Toropov, K. Nesmerak, I. Raska, K. Waisser, K. Palat. Comput. Biol. Chem. 30 (2006) 434–437 2. I. Raska, A. Toropovc. Eur. J. Med. Chem. 41 (2006) 1271–1278 3. P. Thanikaivelan, V. Subramanian, R.J. Raghava, U. Balachandran. Chem. Phys. Lett. 59 (2000) 323-327 4. J. Niu, L. Wang, Z. Yang. Ecotoxicol. Envir. Safety 66 (2007) 272–277 5. ICH Harmonized Tripartite Guideline. Photostability Testing of New Drug Substance and Products. Federal Register, 1996, 62, 27115.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
