Autori: Oprea, Tudor I.; Davis, Andrew M.; Teague, Simon J.; Leeson, Paul D.

Editorial: Journal of Chemical Information and Computer Sciences, 41(5), p.1308-1315, 2001.

Rezumat:

To be considered for further development, lead structures should display the following properties: (1) simple chem. features, amenable for chem. optimization; (2) membership to an established SAR series; (3) favorable patent situation; and (4) good absorption, distribution, metab., and excretion (ADME) properties. There are two distinct categories of leads: those that lack any therapeutic use (i.e., „pure” leads), and those that are marketed drugs themselves but have been altered to yield novel drugs. We have previously analyzed the design of leadlike combinatorial libraries starting from 18 lead and drug pairs of structures (S. J. Teague et al. Angew. Chem., Int. Ed. Engl. 1999, 38, 3743-3748). Here, we report results based on an extended dataset of 96 lead-drug pairs, of which 62 are lead structures that are not marketed as drugs, and 75 are drugs that are not presumably used as leads. We examd. the following properties: MW (mol. wt.), CMR (the calcd. mol. refractivity), RNG (the no. of rings), RTB (the no. of rotatable bonds), the no. of hydrogen bond donors (HDO) and acceptors (HAC), the calcd. logarithm of the n-octanol/water partition (CLogP), the calcd. logarithm of the distribution coeff. at pH 7.4 (LogD74), the Daylight-fingerprint druglike score (DFPS), and the property and pharmacophore features score (PPFS). The following differences were obsd. between the medians of drugs and leads: DMW = 69; DCMR = 1.8; DRNG = DHAC =1; DRTB = 2; DCLogP = 0.43; DLogD74 = 0.97; DHDO = 0; DDFPS = 0.15; DPPFS = 0.12. Lead structures exhibit, on the av., less mol. complexity (less MW, less no. of rings and rotatable bonds), are less hydrophobic (lower CLogP and LogD74), and less druglike (lower druglike scores). These findings indicate that the process of optimizing a lead into a drug results in more complex structures. This information should be used in the design of novel combinatorial libraries that are aimed at lead discovery.

Cuvinte cheie: Combinatorial library, Drug design, Hydrogen bond, Hydrophobicity, Leadlike, Partition, Pharmacophores, Structure-activity relationship