An Impassioned Plea for Smarter Chemical Libraries to Improve Drug Lead Finding

Since the chemical diversity of vendor-supplied libraries is not always relevant to biological function, an earnest plea is being made to the chemical library vendors to advance the chemical methodology and library development technology platform to increase the natural product-like attributes and thus play their part in improving the success of our lead finding efforts.

Go to the profile of Rathnam Chaguturu
Feb 18, 2015
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Drug discovery is a highly complex scientific endeavor, transcended from natural

plant extracts to small molecules, phenotypic observations to target based

approaches, and from random, hit or miss, folklore observations to highly

systematic, targeted efforts. Over the last two decades, the process of new lead

finding almost invariably begins with high-throughput screening of small

molecules against a therapeutic target of interest in a cell-free- or cell-based

assay. Central to every HTS endeavor is the compound collection. These library

collections, about 20 million compounds in all, are designed with a biogenic bias,

primarily on natural product scaffold backbones and selected for drug like

properties and structural diversity. Even though a majority of the marketed drugs

have natural product origins, almost 80% of the core ring scaffolds present

among the natural products are surprisingly absent in the commercially available

screening libraries. Compared with the natural products, combinatorially derived

chemical libraries are highly deficient in chiral centers, low on oxygen atoms and

rich in nitrogen – the key features that dictate target selectivity, specificity and in

vivo metabolism. The wealth of chemical diversity that has evolved with biological

diversity is underrepresented in the commercial chemical library offerings. Since

the chemical diversity of vendor-supplied libraries is not always relevant to

biological function, an earnest plea is being made to the chemical library vendors

to advance the chemical methodology and library development technology

platform to increase the natural product-like attributes and thus play their part in

improving the success of our lead finding efforts. Here are some suggestions:

 New analogs of old drugs, with core and substituent permutations

prioritized according to promising absorption, distribution, metabolism and

excretion (ADME), toxicology and PK profiles;

 A product matrix of common but structurally diverse organic scaffolds:

each scaffold must have demonstrably interesting activities in at least one

assay (but not be active for more than several distinct targets) and be

decorated with a standardized set of substituents chosen to span a

reasonable spectrum of chemical functionality while retaining decent

solubility and cell permeability profiles;

 A collection of diverse heterocycles, including ones whose scaffolds are

drawn from known privileged structures, are reminiscent of privileged

structures, and perhaps including some with little track record in prior

screening as long as there are no previously characterized alert flags

indicative of toxicity, compound aggregation, undue chemical reactivity or

serious ADME liabilities;

 A metabolite-like compound set, with higher polar solubilities, to

overcome bioavailability challenges and increase biogenic bias.

Metabolites tend to be small organics within the metabolome than one

would find in standard screening sets. A lot of these small species are

probably more fragment-like than they are lead-like. In this sense, they

may well be useful, but perhaps at earlier phases in the discovery

process;

 A fragment screening set of small heterocycles, small undecorated

polycyclic, plus various common organic linkers and branching groups that

(at the minimum) collectively embrace the substructural functionality

evident in known small-molecule drugs;

 A collection of small linear and cyclic peptides, including structures with

previously established bioactivity, plus novel oligomers based on helix,

strand, turn and coil structures associated with known protein-interaction

interfaces;

 An extensive and diverse collection of isolated natural products

embracing both known actives as well as novel compounds with promising

solubility and cell permeability profiles; and, last but not least,

 A battery of constitutionally characterized and enriched natural product

extracts.

An ideal general screening library is probably best viewed as an evolving

projection of what is known in chemical biology. Specifically, it: 1) exploits basic

science, 2) rigorously embraces prior experience, and 3) relies on sophisticated

data modeling.

Our wish list of desirable screening compounds discussed above may sound

rational and comprehensive, but the precise formulation of a real library rests on

assumptions that may not yet be practicable. How can we assume that a

compound that has not yet been thoroughly characterized in vivo will have

suitable ADME, toxicology and PK profiles? How exactly do we ensure structural

diversity? How can we infer from known privileged heterocycles other scaffolds

that will have similar biological attributes? This brings us to the crux of the matter:

how do we systematically pursue the formulation of screening sets optimized for

chemical diversity, screening viability and downstream pharmacological aptitude?

Will informatics lead the way? Practical experience? Robust basic science?

The time is now and the need is great to build tailored, smarter screening

libraries based on principles of intelligence and efficiency to meet real 21st

century therapeutics challenges. Let us debate and add value to this discussion

through your input. (For a detailed review of the ideas discussed here, please refer to

Lushington, G and Chaguturu, R. Future Med. Chem. (2014) 6(5), 497–502).

Go to the profile of Rathnam Chaguturu

Rathnam Chaguturu

Dr, iDDPartners

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