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Computational and Experimental Models for the Prediction of Intestinal Drug Solubility and Absorption
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

New effective experimental techniques in medicinal chemistry and pharmacology have resulted in a vast increase in the number of pharmacologically interesting compounds. However, the number of new drugs undergoing clinical trial has not augmented at the same pace, which in part has been attributed to poor absorption of the compounds.

The main objective of this thesis was to investigate whether computer-based models devised from calculated molecular descriptors can be used to predict aqueous drug solubility, an important property influencing the absorption process. For this purpose, both experimental and computational studies were performed. A new small-scale shake flask method for experimental solubility determination of crystalline compounds was devised. This method was used to experimentally determine solubility values used for the computational model development and to investigate the pH-dependent solubility of drugs. In the computer-based studies, rapidly calculated molecular descriptors were used to predict aqueous solubility and the melting point, a solid state characteristic of importance for the solubility. To predict the absorption process, drug permeability across the intestinal epithelium was also modeled.

The results show that high quality solubility data of crystalline compounds can be obtained by the small-scale shake flask method in a microtiter plate format. The experimentally determined pH-dependent solubility profiles deviated largely from the profiles predicted by a traditionally used relationship, highlighting the risk of data extrapolation. The in silico solubility models identified the non-polar surface area and partitioned total surface areas as potential new molecular descriptors for solubility. General solubility models of high accuracy were obtained when combining the surface area descriptors with descriptors for electron distribution, connectivity, flexibility and polarity. The used descriptors proved to be related to the solvation of the molecule rather than to solid state properties. The surface area descriptors were also valid for permeability predictions, and the use of the solubility and permeability models in concert resulted in an excellent theoretical absorption classification. To summarize, the experimental and computational models devised in this thesis are improved absorption screening tools applicable to the lead optimization in the drug discovery process.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 65
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 295
Keywords [en]
Pharmaceutics, aqueous drug solubility, melting point, intestinal drug permeability, pH-dependent solubility, multivariate data analysis, molecular descriptors, molecular surface area, in silico modeling, drug absorption
Keywords [sv]
Galenisk farmaci
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-3593ISBN: 91-554-5747-9 (print)OAI: oai:DiVA.org:uu-3593DiVA, id: diva2:163365
Public defence
2003-10-24, B42, Uppsala Biomedicinska Centrum, Uppsala, 13:00
Opponent
Supervisors
Available from: 2003-09-30 Created: 2003-09-30 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Experimental and computational screening models for prediction of aqueous drug solubility
Open this publication in new window or tab >>Experimental and computational screening models for prediction of aqueous drug solubility
2002 In: Pharmaceutical Research, Vol. 19, no 2, p. 182-188Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90857 (URN)
Available from: 2003-09-30 Created: 2003-09-30Bibliographically approved
2. Absorption classification of oral drugs based on molecular surface properties
Open this publication in new window or tab >>Absorption classification of oral drugs based on molecular surface properties
Show others...
2003 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 46, no 4, p. 558-570Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate whether easily calculated and comprehended molecular surface properties can predict drug solubility and permeability with sufficient accuracy to allow theoretical absorption classification of drug molecules. For this purpose, structurally diverse, orally administered model drugs were selected from the World Health Organization (WHO)'s list of essential drugs. The solubility and permeability of the drugs were determined using well-established in vitro methods in highly accurate experimental settings. Descriptors for molecular surface area were generated from low-energy conformations obtained by conformational analysis using molecular mechanics calculations. Correlations between the calculated molecular surface area descriptors, on one hand, and solubility and permeability, on the other, were established with multivariate data analysis (partial least squares projection to latent structures (PLS)) using training and test sets. The obtained models were challenged with external test sets. Both solubility and permeability of the druglike molecules could be predicted with high accuracy from the calculated molecular surface properties alone. The established correlations were used to perform a theoretical biopharmaceutical classification of the WHO-listed drugs into six classes, resulting in a correct prediction for 87% of the essential drugs. An external test set consisting of Food and Drug Administration (FDA) standard compounds for biopharmaceutical classification was predicted with 77% accuracy. We conclude that PLS models of easily comprehended molecular surface properties can be used to rapidly provide absorption profiles of druglike molecules early on in drug discovery.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90858 (URN)10.1021/jm020986i (DOI)12570377 (PubMedID)
Available from: 2003-09-30 Created: 2003-09-30 Last updated: 2017-12-14Bibliographically approved
3. Global and local computational models for aqueous solubility prediction of drug-like molecules
Open this publication in new window or tab >>Global and local computational models for aqueous solubility prediction of drug-like molecules
Show others...
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-90859 (URN)
Available from: 2003-09-30 Created: 2003-09-30Bibliographically approved
4. Molecular descriptors influencing melting point and their role in classification of solid drugs
Open this publication in new window or tab >>Molecular descriptors influencing melting point and their role in classification of solid drugs
2003 In: Journal of Chemical Information and Computer Sciences, Vol. 43, no 4, p. 1177-1185Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90860 (URN)
Available from: 2003-09-30 Created: 2003-09-30Bibliographically approved
5. Accuracy of calculated pH-dependent aqueous drug solubility
Open this publication in new window or tab >>Accuracy of calculated pH-dependent aqueous drug solubility
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-90861 (URN)
Available from: 2003-09-30 Created: 2003-09-30Bibliographically approved

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