PARTİSYON KATSAYISI (LOG P) TAHMİNİNDE KULLANILAN YAZILIMLARIN KARŞILAŞTIRILMASI

Mehmet Murat Kışla; İlkay Yildiz

doi:10.33483/jfpau.519851

Research Article

PARTİSYON KATSAYISI (LOG P) TAHMİNİNDE KULLANILAN YAZILIMLARIN KARŞILAŞTIRILMASI

Year 2019, Volume: 43 Issue: 1, 1 - 19, 31.01.2019

Mehmet Murat Kışla , İlkay Yildiz

Abstract

Amaç: Sentezlenecek
ilaç etken maddesi adayı bileşiklerin vücut dokularına ulaşabilmesi ve
ulaştığında da toksik etki göstermemesi gerekmektedir. Kantitatif yapı-etki
ilişkilerinin fizikokimyasal parametreler başlığında yer alan partisyon
katsayısı (log P), ilacın farmakokinetik özelliklerini etkilemektedir.
Araştırmacılar, ilaç geliştirme çalışmalarında zaman ve maliyetten tasarruf
sağlamak amacıyla log P tahmin eden yazılımlara başvurabilmektedir. Fakat bu
yazılımların tamamen doğru sonuç vermediği unutulmamalıdır. Bu çalışmada,
kullanılmakta olan bu yazılımların güvenilirliği test edilmiştir. Bunlardan
güvenilirliği onaylanan yazılım araştırmacılara partisyon katsayısının deneysel
tayininden önce fikir verebilecektir.

Gereç ve Yöntem: 94
bileşikten oluşan bileşik verisetinde, literatürdeki log P değerleri ile
ACD/iLab 2.0, ALOGPS 2.1 ve Molinspiration log P yazılımları aracılığıyla
hesaplanan değerler karşılaştırılmış; sapma değerlerine göre bu üç yazılımdan
en güvenilir olan seçilmiştir. Bileşiklerin partisyon katsayısı hesaplanırken
SMILES kodları kullanılmıştır.

Sonuç ve Tartışma: 94 literatür bileşiğinden elde edilen hesaplama sonuçlarına göre
partisyon katsayısı (log P) hesaplamada en güvenilir yazılımın, en düşük
ortalama sapmaya sahip olan Molinspiration log P olduğuna karar verilmiştir. Bu
yazılımın kullanılmasıyla araştırmacılar, sentezlenen bileşiklerin partisyon
katsayısı hakkında yorum yürütebilecek olup, zaman ve maliyetten tasarruf
edebileceklerdir.

Keywords

ADME/Tox, Farmakokinetik, İlaç Geliştirme, Lipofiliklik, Log P

References

Chiang, P., Hu, Y. (2009). Simultaneous Determination of LogD, LogP, and pKa of Drugs by Using a Reverse Phase HPLC Coupled with a 96-Well Plate Auto Injector, Combinatorial Chemistry & High Throughput Screening, 12: 250-257.
Mannhold, R., Poda, G.I., Ostermann, C., Tetko, I.V. (2009). Calculation of molecular lipophilicity: state-of-the-art and comparison of logP methods on more than 96,000 compounds. Journal of Pharmaceutical Sciences., 98: 861–893.
Moriguchi, I., Hirono, S., Nakagome, I., Hirano, H. (1994). Comparison of Reliability of log P Values for Drugs Calculated by Several Methods. Chemical and Pharmaceutical Bulletin, 42: 976-978.
Ghose, A.K. (1998). Prediction of Hydrophobic (Lipophilic) Properties of Small Organic Molecules Using Fragmental Methods: An Analysis of ALOGP and CLOGP Methods. The Journal of Physical Chemistry A, 102: 3762-3772.
Abraham, M.H., McGowan, J.C. (1987). The use of characteristic volumes to measure cavity terms in reversed phase liquid chromatography. Chromatographia 23: 243-246.
Figueroa-Valverde, L., Diaz-Cedillo, F., Lopez Ramos, M. (2011). Synthesis of pregnenolone–danazol–ethylendiamine conjugate: relationship between descriptors log P, p, Rm, and Vm and its antibacterial activity in S. aureus and V. Cholerae, Medicinal Chemistry Research, 20: 847–853.
Figueroa-Valverde, L., Diaz-Cedillo F., Camacho-Luis, A., Lopez Ramos, M., Garcia Cervera E. (2010). Synthesis of a dihydrotestosterone–ciprofloxacin conjugate: relationship between descriptors logP, p, Rm, and Vm and its antibacterial activity in S. aureus and E. Coli, Monatshefte für Chemie, 141: 373–380.
Glover, S.A., Schumacher, R.R. (2016). The effect of hydrophobicity upon the direct mutagenicity of N-acyloxy-N-alkoxyamides—Bilinear dependence upon LogP, Mutation Research, 795: 41–50.
Abrego, V.H., Martínez-Pérez, B., Torres, L.A., Angeles, E., Martínez, L., Marroquín-Pascual, J.L., Moya-Hernández, R., Amaro-Recillas, H.A., Rueda-Jackson, J.C., Rodríguez-Barrientos, D., Rojas-Hernández, A. (2010). Antihypertensive and antiarrhythmic properties of a para-hydroxy[bis(ortho-morpholinylmethyl)]phenyl-1,4-DHP compound: comparison with other compounds of the same kind and relationship with logP values, European Journal of Medicinal Chemistry, 45: 4622- 4630.
Zhou, S., Yang, S., Huang, G. (2017). Design, synthesis and bioactivities of Celecoxib analogues or derivatives, Bioorganic & Medicinal Chemistry, 25: 4887–4893.
Wu, Y.C., Luo, S.H., Mei, W.J., Cao, L., Wu, H.Q., Wang, Z.Y. (2017). Synthesis and biological evaluation of 4-biphenylamino-5-halo-2(5H)-furanones as potential anticancer agents, European Journal of Medicinal Chemistry, 139: 84-94.
ACD/iLab, version 2.0 (2015). Advanced Chemistry Development, Inc., Toronto, ON, Canada, www.acdlabs.com.
VCCLAB (2005). Virtual Computational Chemistry Laboratory, http://www.vcclab.org.
Molinspiration Log P, (2017). Calculation of Molecular Properties and Bioactivity Score, http://www.molinspiration.com/cgi-bin/properties.
Petrauskas, A., Kolovanov, E. (2000). ACD/Log P Method Description. Persp. in Drug Design, 19:1–19.
Tetko, I. V.; Tanchuk, V. Y. (2002). Application of associative neural networks for prediction of lipophilicity in ALOGPS 2.1 program, Journal of Chemical Information and Computer Sciences, 42, 1136-45.
Tetko, I. V.; Tanchuk, V. Y.; Villa, A. E. (2001). Prediction of n-octanol/water partition coefficients from PHYSPROP database using artificial neural networks and E-state indices, Journal of Chemical Information and Computer Sciences, 41, 1407-21.
Bundgaard, H., Falch, E. (1985). Allopurinol prodrugs. I. Synthesis, stability and physicochemical properties of various N1-acyl allopurinol derivatives, International Journal of Pharmaceutics, 23, Issue 2: 223-237.
Sangster, J. . (1994) LOGKOW Databank. Montreal Quebec, Canada: Sangster Res. Lab.
Kim, S., Thiessen, P.A., Bolton, E.E., Chen, J., Fu, G., Gindulyte, A., Han, L., He, J., He, S., Shoemaker, B.A., Wang, J., Yu, B., Zhang, J., Bryant, S.H. (2016). PubChem Substance and Compound databases, Nucleic Acids Res., 44:202-13.
El Tayar, N., Waterbeemd, H., Testa, B. (1985). Lipophilicity measurements of protonated basic compounds by reversed-phase high-performance liquid chromatography: I. Relationship between capacity factors and the methanol concentration in methanol-water eluents, Journal of Chromatography A, 320, Issue 2: 293-304.
Kristl, A., Mrhar, A., Kozjek, F. (1993). The ionisation properties of acyclovir and deoxyacyclovir, International Journal of Pharmaceutics, 99, Issue 1, 79- 82.
McFarland, J.W., Berger, C.M., Froshauer, S.A., Hayashi, S.F., Hecker, SJ, Jaynes, BH, Jefson, MR, Kamicker, BJ, Lipinski, CA, Lundy, KM, Reese, CP, Vu, CB. (1997). Quantitative structure-activity relationships among macrolide antibacterial agents: in vitro and in vivo potency against Pasteurella multocida. Journal of Medicinal Chemistry, 40(9): 1340-6.
Takacs- Novak, K., Avdeef, A. (1996). Interlaboratory study of log {ce:inline-formula}P{/ce:inline-formula} determination by shake-flask and potentiometric methods, Journal of Pharmaceutical and Biomedical Analysis, 14, Issue 11: 1405-1413.
Hansch, C., Leo, A., Hoekman, D. (1995). Exploring QSAR Fundamentals and Applications in Chemistry and Biology, Volume 1. Hydrophobic, Electronic and Steric Constants, Volume 2, Journal of the American Chemical Society, 117.
Avdeef, A., Box, K.J., Comer, J.E.A., Hibbert, C., Tam, K.Y. (1997). pH-metric log P. 10. Determination of vesicle membrane – water partition coefficients of ionizable drugs. Pharmaceutical Research, 15: 208-214.
Wishart, D.S., Feunang, Y.D., Guo, A.C., Lo, E.J., Marcu, A., Grant, J.R., Sajed, T., Johnson, D., Li, C., Sayeeda, Z., Assempour, N., Iynkkaran, I., Liu, Y., Maciejewski, A., Gale, N., Wilson, A., Chin, L., Cummings, R., Le, D., Pon, A., Knox, C., Wilson, M. (2017). DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Research.
Dal Pozzo, A., Donzelli, G., Rodriquez, L., Tajana, A. (1989). “In vitro” model for the evaluation of drug distribution and plasma protein-binding relationships, International Journal of Pharmaceutics, 50, Issue 2: 97- 101.
Medic-Saric, M., Jasprica, A.M.I. (2004). Lipophilicity study of salicylamide, Acta Pharmaceutica. 54: 91–101.

COMPARISON OF PARTITION COEFFICIENT (LOG P) PREDICTION SOFTWARES

Year 2019, Volume: 43 Issue: 1, 1 - 19, 31.01.2019

Mehmet Murat Kışla , İlkay Yildiz

Abstract

Objective: Drug candidate compounds that are going to be
synthesized have to reach body tissues and show minimum toxic effects within
the body. Partition coefficient (log P), which is a physicochemical parameter
of Quantitative Structure- Activity Relationship subject, effects the
pharmacokinetical characteristic of the compound. In this context, researchers
tend to use log P prediction softwares to save both time and resources in their
drug development studies. Although, these softwares do not give a true value.
In this study, softwares that have being used were tested. The one that gets
approved for its accuracy can give some clues on the value of partition
coefficient, before determining it experimentally.

Material and Method: In the following dataset, which
comprises of 94 compounds, logP values from literature and values that have
been calculated with softwares such as ACD/iLab 2.0, ALOGPS 2.1 ve
Molinspiration have been compared. By calculating the deviations, most reliable
of these three has been selected. SMILES notations of the compounds has been
used as an input for the calculation.

Result and Discussion: According to the calculation results of 94 compounds, Molinspiration log
P, which has the lowest average deviation value, was selected as most reliable
log P prediction software. By using this software, scholars can comment on
partition coefficients of their synthesized compounds. Therefore, hopefully
they can save both time and resources.

Keywords

ADME/Tox, Drug Development, Lipophilicity, Log P, Pharmacokinetics

References

Chiang, P., Hu, Y. (2009). Simultaneous Determination of LogD, LogP, and pKa of Drugs by Using a Reverse Phase HPLC Coupled with a 96-Well Plate Auto Injector, Combinatorial Chemistry & High Throughput Screening, 12: 250-257.
Mannhold, R., Poda, G.I., Ostermann, C., Tetko, I.V. (2009). Calculation of molecular lipophilicity: state-of-the-art and comparison of logP methods on more than 96,000 compounds. Journal of Pharmaceutical Sciences., 98: 861–893.
Moriguchi, I., Hirono, S., Nakagome, I., Hirano, H. (1994). Comparison of Reliability of log P Values for Drugs Calculated by Several Methods. Chemical and Pharmaceutical Bulletin, 42: 976-978.
Ghose, A.K. (1998). Prediction of Hydrophobic (Lipophilic) Properties of Small Organic Molecules Using Fragmental Methods: An Analysis of ALOGP and CLOGP Methods. The Journal of Physical Chemistry A, 102: 3762-3772.
Abraham, M.H., McGowan, J.C. (1987). The use of characteristic volumes to measure cavity terms in reversed phase liquid chromatography. Chromatographia 23: 243-246.
Figueroa-Valverde, L., Diaz-Cedillo, F., Lopez Ramos, M. (2011). Synthesis of pregnenolone–danazol–ethylendiamine conjugate: relationship between descriptors log P, p, Rm, and Vm and its antibacterial activity in S. aureus and V. Cholerae, Medicinal Chemistry Research, 20: 847–853.
Figueroa-Valverde, L., Diaz-Cedillo F., Camacho-Luis, A., Lopez Ramos, M., Garcia Cervera E. (2010). Synthesis of a dihydrotestosterone–ciprofloxacin conjugate: relationship between descriptors logP, p, Rm, and Vm and its antibacterial activity in S. aureus and E. Coli, Monatshefte für Chemie, 141: 373–380.
Glover, S.A., Schumacher, R.R. (2016). The effect of hydrophobicity upon the direct mutagenicity of N-acyloxy-N-alkoxyamides—Bilinear dependence upon LogP, Mutation Research, 795: 41–50.
Abrego, V.H., Martínez-Pérez, B., Torres, L.A., Angeles, E., Martínez, L., Marroquín-Pascual, J.L., Moya-Hernández, R., Amaro-Recillas, H.A., Rueda-Jackson, J.C., Rodríguez-Barrientos, D., Rojas-Hernández, A. (2010). Antihypertensive and antiarrhythmic properties of a para-hydroxy[bis(ortho-morpholinylmethyl)]phenyl-1,4-DHP compound: comparison with other compounds of the same kind and relationship with logP values, European Journal of Medicinal Chemistry, 45: 4622- 4630.
Zhou, S., Yang, S., Huang, G. (2017). Design, synthesis and bioactivities of Celecoxib analogues or derivatives, Bioorganic & Medicinal Chemistry, 25: 4887–4893.
Wu, Y.C., Luo, S.H., Mei, W.J., Cao, L., Wu, H.Q., Wang, Z.Y. (2017). Synthesis and biological evaluation of 4-biphenylamino-5-halo-2(5H)-furanones as potential anticancer agents, European Journal of Medicinal Chemistry, 139: 84-94.
ACD/iLab, version 2.0 (2015). Advanced Chemistry Development, Inc., Toronto, ON, Canada, www.acdlabs.com.
VCCLAB (2005). Virtual Computational Chemistry Laboratory, http://www.vcclab.org.
Molinspiration Log P, (2017). Calculation of Molecular Properties and Bioactivity Score, http://www.molinspiration.com/cgi-bin/properties.
Petrauskas, A., Kolovanov, E. (2000). ACD/Log P Method Description. Persp. in Drug Design, 19:1–19.
Tetko, I. V.; Tanchuk, V. Y. (2002). Application of associative neural networks for prediction of lipophilicity in ALOGPS 2.1 program, Journal of Chemical Information and Computer Sciences, 42, 1136-45.
Tetko, I. V.; Tanchuk, V. Y.; Villa, A. E. (2001). Prediction of n-octanol/water partition coefficients from PHYSPROP database using artificial neural networks and E-state indices, Journal of Chemical Information and Computer Sciences, 41, 1407-21.
Bundgaard, H., Falch, E. (1985). Allopurinol prodrugs. I. Synthesis, stability and physicochemical properties of various N1-acyl allopurinol derivatives, International Journal of Pharmaceutics, 23, Issue 2: 223-237.
Sangster, J. . (1994) LOGKOW Databank. Montreal Quebec, Canada: Sangster Res. Lab.
Kim, S., Thiessen, P.A., Bolton, E.E., Chen, J., Fu, G., Gindulyte, A., Han, L., He, J., He, S., Shoemaker, B.A., Wang, J., Yu, B., Zhang, J., Bryant, S.H. (2016). PubChem Substance and Compound databases, Nucleic Acids Res., 44:202-13.
El Tayar, N., Waterbeemd, H., Testa, B. (1985). Lipophilicity measurements of protonated basic compounds by reversed-phase high-performance liquid chromatography: I. Relationship between capacity factors and the methanol concentration in methanol-water eluents, Journal of Chromatography A, 320, Issue 2: 293-304.
Kristl, A., Mrhar, A., Kozjek, F. (1993). The ionisation properties of acyclovir and deoxyacyclovir, International Journal of Pharmaceutics, 99, Issue 1, 79- 82.
McFarland, J.W., Berger, C.M., Froshauer, S.A., Hayashi, S.F., Hecker, SJ, Jaynes, BH, Jefson, MR, Kamicker, BJ, Lipinski, CA, Lundy, KM, Reese, CP, Vu, CB. (1997). Quantitative structure-activity relationships among macrolide antibacterial agents: in vitro and in vivo potency against Pasteurella multocida. Journal of Medicinal Chemistry, 40(9): 1340-6.
Takacs- Novak, K., Avdeef, A. (1996). Interlaboratory study of log {ce:inline-formula}P{/ce:inline-formula} determination by shake-flask and potentiometric methods, Journal of Pharmaceutical and Biomedical Analysis, 14, Issue 11: 1405-1413.
Hansch, C., Leo, A., Hoekman, D. (1995). Exploring QSAR Fundamentals and Applications in Chemistry and Biology, Volume 1. Hydrophobic, Electronic and Steric Constants, Volume 2, Journal of the American Chemical Society, 117.
Avdeef, A., Box, K.J., Comer, J.E.A., Hibbert, C., Tam, K.Y. (1997). pH-metric log P. 10. Determination of vesicle membrane – water partition coefficients of ionizable drugs. Pharmaceutical Research, 15: 208-214.
Wishart, D.S., Feunang, Y.D., Guo, A.C., Lo, E.J., Marcu, A., Grant, J.R., Sajed, T., Johnson, D., Li, C., Sayeeda, Z., Assempour, N., Iynkkaran, I., Liu, Y., Maciejewski, A., Gale, N., Wilson, A., Chin, L., Cummings, R., Le, D., Pon, A., Knox, C., Wilson, M. (2017). DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Research.
Dal Pozzo, A., Donzelli, G., Rodriquez, L., Tajana, A. (1989). “In vitro” model for the evaluation of drug distribution and plasma protein-binding relationships, International Journal of Pharmaceutics, 50, Issue 2: 97- 101.
Medic-Saric, M., Jasprica, A.M.I. (2004). Lipophilicity study of salicylamide, Acta Pharmaceutica. 54: 91–101.

There are 29 citations in total.

Details

Primary Language	Turkish
Journal Section	Research Article
Authors	Mehmet Murat Kışla İlkay Yildiz
Publication Date	January 31, 2019
Submission Date	September 26, 2018
Acceptance Date	January 30, 2019
Published in Issue	Year 2019 Volume: 43 Issue: 1

Cite

APA	Kışla, M. M., & Yildiz, İ. (2019). PARTİSYON KATSAYISI (LOG P) TAHMİNİNDE KULLANILAN YAZILIMLARIN KARŞILAŞTIRILMASI. Journal of Faculty of Pharmacy of Ankara University, 43(1), 1-19. https://doi.org/10.33483/jfpau.519851
AMA	Kışla MM, Yildiz İ. PARTİSYON KATSAYISI (LOG P) TAHMİNİNDE KULLANILAN YAZILIMLARIN KARŞILAŞTIRILMASI. J. Fac. Pharm. Ankara. January 2019;43(1):1-19. doi:10.33483/jfpau.519851
Chicago	Kışla, Mehmet Murat, and İlkay Yildiz. “PARTİSYON KATSAYISI (LOG P) TAHMİNİNDE KULLANILAN YAZILIMLARIN KARŞILAŞTIRILMASI”. Journal of Faculty of Pharmacy of Ankara University 43, no. 1 (January 2019): 1-19. https://doi.org/10.33483/jfpau.519851.
EndNote	Kışla MM, Yildiz İ (January 1, 2019) PARTİSYON KATSAYISI (LOG P) TAHMİNİNDE KULLANILAN YAZILIMLARIN KARŞILAŞTIRILMASI. Journal of Faculty of Pharmacy of Ankara University 43 1 1–19.
IEEE	M. M. Kışla and İ. Yildiz, “PARTİSYON KATSAYISI (LOG P) TAHMİNİNDE KULLANILAN YAZILIMLARIN KARŞILAŞTIRILMASI”, J. Fac. Pharm. Ankara, vol. 43, no. 1, pp. 1–19, 2019, doi: 10.33483/jfpau.519851.
ISNAD	Kışla, Mehmet Murat - Yildiz, İlkay. “PARTİSYON KATSAYISI (LOG P) TAHMİNİNDE KULLANILAN YAZILIMLARIN KARŞILAŞTIRILMASI”. Journal of Faculty of Pharmacy of Ankara University 43/1 (January 2019), 1-19. https://doi.org/10.33483/jfpau.519851.
JAMA	Kışla MM, Yildiz İ. PARTİSYON KATSAYISI (LOG P) TAHMİNİNDE KULLANILAN YAZILIMLARIN KARŞILAŞTIRILMASI. J. Fac. Pharm. Ankara. 2019;43:1–19.
MLA	Kışla, Mehmet Murat and İlkay Yildiz. “PARTİSYON KATSAYISI (LOG P) TAHMİNİNDE KULLANILAN YAZILIMLARIN KARŞILAŞTIRILMASI”. Journal of Faculty of Pharmacy of Ankara University, vol. 43, no. 1, 2019, pp. 1-19, doi:10.33483/jfpau.519851.
Vancouver	Kışla MM, Yildiz İ. PARTİSYON KATSAYISI (LOG P) TAHMİNİNDE KULLANILAN YAZILIMLARIN KARŞILAŞTIRILMASI. J. Fac. Pharm. Ankara. 2019;43(1):1-19.

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The Journal of Faculty of Pharmacy of Ankara University is an international medium, an open access, peer-reviewed journal for the publication of original research reports, reviews and short communications in English or Turkish on relevant developments in pharmaceutical sciences., Proceeding of scientific meetings may be published as special issues of supplements to the journal. Additionally, it contains previous and forthcoming national and international scientific meetings with social activities in pharmaceutical areas.