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In the library, you will find a range of scientific presentations and bibliography presented or written by both Keymodule staff and our users. The library contains several articles and presentations about Keymodule’s products.

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Complexity analysis of de novo designed ligands

Krisztina Boda, A. Peter Johnson

The de novo approach to rational drug design offers a powerful tool to suggest entirely novel potential leads in cases where other drug design methods fail.

However programs for structure generation typically produce large numbers of putative ligands, therefore various heuristics (such as estimation of synthetic accessibility and binding affinity) have to be adopted to evaluate and prune large answer sets with the goal of suggesting ligands with high affinity but low structural complexity. We have developed a method for complexity analysis which provides a fast and effective ranking technique for elimination of structures with unfeasible molecular motifs.

The complexity analysis technique, implemented for the SPROUT de novo design system, is based on the statistical distribution of various cyclic and chain structural motifs and substitution patterns in existing drugs. The complexity score for a putative ligand is calculated by matching structural features against those of compounds in a database of drug molecules.

The novel feature of our technique that distinguishes it from other published methods is that the matching takes place at various levels of abstraction, so that it can evaluate complexity scores for partially substituted structures which is the case in SPROUT where molecular structures are built in stepwise fashion utilising a small library of generic and specific building blocks.

The presentation will include examples of applications of the technique to problems in structure based drug design.


Molecular complexity analysis of de novo designed ligands

Krisztina Boda, A. Peter Johnson


Scoring synthetic feasibility: A very different problem

A. Peter Johnson, Krisztina Boda, Glenn J. Myatt, J. Christian Baber

A huge amount of effort has gone into the problem of predicting the binding affinity of given poses of hypothetical ligands docked to protein binding sites. However, if these hypothetical ligands have been produced by de novo design, an equally important consideration is whether they are synthetically accessible. Over the past decade, we have attempted to address this problem in a variety of ways. The CAESA program combines an empirical approach to molecular complexity with a relatively rapid retrosynthetic analysis to find starting materials, the hypothesis being that complexity contained within readily available starting materials is apparent rather than true complexity. An alternative approach, incorporated into the SPROUT program, analyses structural complexity by comparing substitution patterns of ligand structures with those found in known drugs and databases of commercially available starting materials. The relative merits of these approaches will be discussed.


Molecular modeling in the discovery of drug leads

George W. A. Milne, Shaomeng Wang, and Marc C. Nicklaus


Design, synthesis, and biological evaluation of potent and selective amidino bicyclic factor Xa inhibitors

Qi Han, Celia Dominguez, Pieter F. W. Stouten, Jeongsook M. Park, Daniel E. Duffy, Robert A. Galemmo, Jr., Karen A. Rossi, Richard S. Alexander, Angela M. Smallwood, Pancras C. Wong, Matthew M. Wright, Joseph M. Luettgen, Robert M. Knabb, Ruth R. Wexler


Design, synthesis and SAR of novel and selective T-type calcium channel antagonists containing a biaryl sulfonamide core

Jon J. Hangeland, Todd J. Friends, Daniel L. Cheney, Paul C. Levesque, Adam J. Rich, Lucy Sun, Terry R. Bridal, Leonard P. Adam, Diane E. Normandin


De novo design of novel and selective T-type calcium channel blockers

Daniel L. Cheney, Jon J. Hangeland, Todd J. Friends, Paul C. Levesque


Three for three: De novo design of multiple novel chemotypes of T-type calcium channel blockers

Daniel L. Cheney, Jon J. Hangeland, Todd J. Friends, Paul C. Levesque


The first de novo-designed antagonists of the human NK2 receptor

Mohammed A. Ali, Nirmala Bhogal, John B. C. Findlay, Colin W. G. Fishwick


A novel de novo designed inhibitor of D-ala-D-ala ligase from E.coli.

Gilbert E. Besong, Julieanne M. Bostock, Will Stubbings, Ian Chopra, David I. Roper, Adrian J. Lloyd, Colin W. G. Fishwick, A. Peter Johnson

De novo design and synthesis of novel RNA polymerase inhibitors as potential anti-tuberculosis agents

Anil K. Agarwal, Julian Hurdle, Amer I. AlOmar, Ian Chopra, A. Peter Johnson, Colin W. G. Fishwick

Design and synthesis of new dihydroorotate dehydrogenase inhibitors as potent antimalarials

Matthew Davies, Timo Heikkila, Colin W. G. Fishwick, A. Peter Johnson