Is there a difference between leads and drugs? A historical perspective

To be considered for further development, lead structures should display the following properties: (1) simple chemical features, amenable for chemistry optimization; (2) membership to an established SAR series; (3) favorable patent situation; and (4) good absorption, distribution, metabolism, 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 examined the following properties: MW (molecular weight), CMR (the calculated molecular refractivity), RNG (the number of rings), RTB (the number of rotatable bonds), the number of hydrogen bond donors (HDO) and acceptors (HAC), the calculated logarithm of the n-octanol/water partition (CLogP), the calculated logarithm of the distribution coefficient at pH 7.4 (LogD(74)), the Daylight-fingerprint druglike score (DFPS), and the property and pharmacophore features score (PPFS). The following differences were observed between the medians of drugs and leads: DeltaMW = 69; DeltaCMR = 1.8; DeltaRNG = DeltaHAC =1; DeltaRTB = 2; DeltaCLogP = 0.43; DeltaLogD(74) = 0.97; DeltaHDO = 0; DeltaDFPS = 0.15; DeltaPPFS = 0.12. Lead structures exhibit, on the average, less molecular complexity (less MW, less number of rings and rotatable bonds), are less hydrophobic (lower CLogP and LogD(74)), 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.     

Equationally complete (m,n) rings

It is shown that every super-simple (m, n) ring is equationally complete. The atomic varieties of (m, 2) rings and the atomic varieties of (2,n) rings are completely determined.     

The Design of Leadlike Combinatorial Libraries

The optimization of low-potency leads into drugs is often accompanied by an increase in molecular weight (M(r)) and lipophilicity, as a consequence of affinity enhancement. Hits with affinity at μM levels discovered by screening leadlike libraries allow scope for this optimization process, as shown schematically by the distributions of M(r) for a leadlike library (1), oral drugs (2), and a typical combinatorial chemistry library (3). y=percentage with a particular molecular weight.     

Recruitment Effects on Manpower Structures

Recruitment is one of the dynamics of manpower systems that can usually be most effectively controlled, always assuming that there is at any time an adequate supply of recruits to a system. In this situation, recruitment can be fixed to meet immediate demands, or it can be part of long-term planning programmes designed perhaps to alleviate a skewness in the length of service profile without reducing the strength of the system greatly. In general, recruitment levels will necessarily be connected with wastage and promotion in a system as well as with the desired growth of the system. The process of determining manpower-planning policies, hereunder recruitment levels, is open to a variety of options with regard to the underlying assumptions that are made: observed experience can be assumed to continue; promotion policies can be adjusted and the consequences estimated; recruitment levels can be allowed to meet immediate demands but with the restriction of some maximum level; or recruitment levels are pre-fixed on the basis of some perhaps even arbitrary management desires. Each of these options and each accompanying recruitment policy will affect the internal structure of the system, with regard to both rank and length of service profiles. This paper employs established projection and promotion models for hierarchical manpower systems to consider recruitment policies and their effects on internal structures. Various policy models are outlined and results presented for a particular application.     

A Projection Model for Hierarchical Manpower Systems

This paper presents a projection model for a hierarchical manpower system, viz. a combined group of English County Police Constabularies. The model is designed to describe how observed wastage and promotion rates will shape the internal structure of the system should these persist. Employees in the system are classified according to rank and completed length of service. The model also determines recruitment rates necessary to achieve desired manning levels.     

Manpower planning procedures for hierarchical manpower systems

In this paper, a model which describes manpower planning procedures for a hierarchical system having certain desired properties to be achieved is presented. These properties will act as constraints on the system. It will be assumed that eventual, desired properties are achieved gradually over a period of time. Promotion policies will be wastagelinked and designed to satisfy vacancy-expansion demands. The model will be applied to data from a group of English County Police Constabularies.     

Photophysical properties of Kuratowski-type coordination compounds [M(II)Zn4Cl4(Me2bta)6] (M(II) = Zn or Ru) featuring long-lived excited electronic states

The syntheses of Kuratowski-type pentanuclear clusters featuring {MZn(4)Cl(4)} cores (M(II) = Ru or Zn) that incorporate triazolate ligands are described. The coordination compounds are characterized by single-crystal X-ray diffraction, X-ray powder diffraction (XRD), FTIR- and UV-vis spectroscopy. [Ru(II)Zn(4)Cl(4)(Me(2)bta)(6)]·2DMF (Me(2)bta(-) = 5,6-dimethyl-1,2,3-benzotriazolate) (1) crystallizes in the cubic system, while [Zn(5)Cl(4)(ta)(6)] (ta(-) = 1,2,3-triazolate) (3) crystallizes in the tetragonal system. Both compounds feature structurally similar cluster topologies in which the central octahedrally coordinated metal ion is coordinated to six triazolate ligands. Each triazolate ligand is coordinated with two zinc ions (μ(3)-bridging mode), leading altogether to a pentanuclear cluster of T(d) point group symmetry. Photophysical investigations reveal that compound [Zn(5)Cl(4)(Me(2)bta)(6)]·2DMF (2) shows a short-lived excited electronic state, which can be populated with high quantum yield. The isostructural compound [Ru(II)Zn(4)Cl(4)(Me(2)bta)(6)]·2DMF (1), on the other hand, shows a long-lived photoexcited state, owing to an internal singlet to triplet conversion of the electronic states, as revealed by time-resolved fluorescence spectroscopy. Insights gained from these studies open up novel design strategies towards photocatalytically active metal-organic frameworks incorporating photoactive Kuratowski-type secondary building units such as MFU-4 (Metal-Organic Framework Ulm University-4).