Computer-assisted design of new drugs based on retrometabolic concepts

被引:26
作者
Bodor, N [1 ]
Buchwald, P [1 ]
Huang, MJ [1 ]
机构
[1] Univ Florida, Hlth Sci Ctr, Ctr Drug Discovery, Gainesville, FL 32610 USA
关键词
retrometabolic design; soft drug; chemical delivery system; peptide delivery; partition coefficient;
D O I
10.1080/10629369808033261
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Retrometabolic drug design approaches incorporate metabolic and toxicological considerations into the drug design process and represent a novel, systematic methodology for the design of safe compounds. Two major design concepts aimed to increase the therapeutic index (the activity/toxicity ratio) of drugs were developed. Chemical delivery systems (CDS) are primarily used to allow targeting of the active biological molecules to specific target sites or organs based on predictable enzymatic activation. Sofi drug approaches are used to design new drugs by building in the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified subsequent to exerting its biological effects. Special computer programs were developed that starting from a lead compound generate complete libraries of possible soft analogs and then help ranking these candidates based on isosteric-isoelectronic comparisons, predicted solubility/partition properties, and estimated metabolic rates. The novel field of large peptide-CDSs imposes special challenges, but a new, remarkably simple model was developed to estimate partition properties for a wide range of compounds, including quite large peptide derivatives. A suggested change of about five order of magnitudes in the distribution coefficient can explain the "lock in" mechanism of brain-targeting delivery systems.
引用
收藏
页码:41 / +
页数:54
相关论文
共 131 条
[91]   THE OCTANOL WATER PARTITION-COEFFICIENT OF AROMATIC SOLUTES - THE EFFECT OF ELECTRONIC INTERACTIONS, ALKYL CHAINS, HYDROGEN-BONDS, AND ORTHO-SUBSTITUTION [J].
LEO, A .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2, 1983, (06) :825-838
[92]   PARTITION COEFFICIENTS AND THEIR USES [J].
LEO, A ;
HANSCH, C ;
ELKINS, D .
CHEMICAL REVIEWS, 1971, 71 (06) :525-+
[93]   CALCULATING LOG P(OCT) FROM STRUCTURES [J].
LEO, AJ .
CHEMICAL REVIEWS, 1993, 93 (04) :1281-1306
[94]  
LEO AJ, 1990, COMPREHENSIVE MED CH, V4, P295
[95]  
LEVINE IN, 1989, PHYSICAL CHEM, P805
[96]  
LITTLE R, 1990, J BIOPHARM SCI, V1, P1
[97]   ENTHALPY-ENTROPY COMPENSATION PHENOMENA IN WATER SOLUTIONS OF PROTEINS AND SMALL MOLECULES - A UBIQUITOUS PROPERTY OF WATER [J].
LUMRY, R ;
RAJENDER, S .
BIOPOLYMERS, 1970, 9 (10) :1125-&
[98]   RELATIONSHIPS BETWEEN AQUEOUS SOLUBILITY AND OCTANOL-WATER PARTITION-COEFFICIENTS [J].
MACKAY, D ;
BOBRA, A ;
SHIU, WY ;
YALKOWSKY, SH .
CHEMOSPHERE, 1980, 9 (11) :701-711
[99]   COMPARATIVE-EVALUATION OF THE PREDICTIVE POWER OF CALCULATION PROCEDURES FOR MOLECULAR LIPOPHILICITY [J].
MANNHOLD, R ;
REKKER, RF ;
SONNTAG, C ;
TERLAAK, AM ;
DROSS, K ;
POLYMEROPOULOS, EE .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1995, 84 (12) :1410-1419
[100]   A RANDOM-WALK THROUGH A CANNABIS FIELD [J].
MECHOULAM, R ;
DEVANE, WA ;
BREUER, A ;
ZAHALKA, J .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 1991, 40 (03) :461-464