Jin Li

PRO_LIGAND: An approach to de novo molecular design. 1. Application to the design of organic molecules

SummaryAn approach to de novo molecular design, PRO_LIGAND, has been developed that, in the environment of a large, integrated molecular design and simulation system, provides a unified framework for the generation of novel molecules which are either similar or complementary to a specified target. The approach is based on a methodology that has proved to be effective in other studies-placing molecular fragments upon target interaction sites-but incorporates many novel features such as the use of a rapid graph-theoretical algorithm for fragment placing, a generalised driver for structure generation which offers a large variety of fragment assembly strategies to the user and the pre-screening of library fragments. After a detailed description of the relevant modules of the package, PRO_LIGANDs efficacy in aiding rational drug design is demonstrated by its ability to design mimics of methotrexate and potential inhibitors for dihydrofolate reductase and HIV-1 protease.

Large-scale virtual screening for discovering leads in the postgenomic era

Virtual screening, or in silico screening, is a new approach attracting increasing levels of interest in the pharmaceutical industry as a productive and cost-effective technology in the search for novel lead compounds. Although the principles involved--the computational analysis of chemical databases to identify compounds appropriate for a given biological receptor--have been pursued for several years in molecular modeling groups, the availability of inexpensive high-performance computing platforms has transformed the process so that increasingly complex and more accurate analyses can be performed on very large data sets. The virtual screening technology of Protherics Molecular Design Ltd. is based on its integrated software environment for receptor-based drug design, called Prometheus. In particular, molecular docking is used to predict the binding modes and binding affinities of every compound in the data set to a given biological receptor. This method represents a very detailed and relevant basis for prioritizing compounds for biological screening. This paper discusses the broader scope of virtual screening and, as an example, describes our recent work in docking one million compounds into the estrogen hormone receptor in order to highlight the technical feasibility of performing very large-scale virtual screening as a route to identifying novel drug leads.

PRO_SELECT: Combining structure-based drug design and combinatorial chemistry for rapid lead discovery. 1. Technology

This paper describes a novel methodology, PRO_SELECT, which combines elements of structure-based drug design and combinatorial chemistry to create a new paradigm for accelerated lead discovery. Starting with a synthetically accessible template positioned in the active site of the target of interest, PRO_SELECT employs database searching to generate lists of potential substituents for each substituent position on the template. These substituents are selected on the basis of their being able to couple to the template using known synthetic routes and their possession of the correct functionality to interact with specified residues in the active site. The lists of potential substituents are then screened computationally against the active site using rapid algorithms. An empirical scoring function, correlated to binding free energy, is used to rank the substituents at each position. The highest scoring substituents at each position can then be examined using a variety of techniques and a final selection is made. Combinatorial enumeration of the final lists generates a library of synthetically accessible molecules, which may then be prioritised for synthesis and assay. The results obtained using PRO_SELECT to design thrombin inhibitors are briefly discussed.

PRO_LIGAND: An approach to de novo molecular design. 3. A genetic algorithm for structure refinement

SummaryRecently, the development of computer programs which permit the de novo design of molecular structures satisfying a set of steric and chemical constraints has become a burgeoning area of research and many operational systems have been reported in the literature. Experience with PRO_LIGAND—the de novo design methodology embodied in our in-house molecular design and simulation system PRO-METHEUS—has suggested that the addition of a genetic algorithm (GA) structure refinement procedure can ‘add value’ to an already useful tool. Starting with the set of designed molecules as an initial population, the GA can combine features from both high- and low-scoring structures and, over a number of generations, produce individuals of better score than any of the starting structures. This paper describes how we have implemented such a procedure and demonstrates its efficacy in improving two sets of molecules generated by different de novo design projects.

Targeted molecular diversity in drug discovery: Integration of structure-based design and combinatorial chemistry

A powerful new approach emerging in drug discovery research combines computational screening of virtual combinatorial libraries against a therapeutic target and targeted combinatorial library synthesis. This new approach includes positive features from both structure-based design and combinatorial chemistry. It has the potential of producing combinatorial libraries with a high hit rate, and hence accelerates the generation of quality lead compounds. The effectiveness of this novel approach has been shown by the design and synthesis of potent inhibitors for serine and aspartyl proteases.

PRO_LIGAND: An approach to de novo molecular design. 4. Application to the design of peptides

SummaryIn some instances, peptides can play an important role in the discovery of lead compounds. This paper describes the peptide design facility of the de novo drug design package, PRO_LIGAND. The package provides a unified framework for the design of peptides that are similar or complementary to a specified target. The approach uses single amino acid residues, selected from preconstructed libraries of different residues and conformations, and places them on top of predefined target interaction sites. This approach is a well-tested methodology for the design of organics but has not been used for peptides before. Peptides represent a difficulty because of their great conformational flexibility and a study of the advantages and disavantages of this simple approach is an important step in the development of design tools. After a description of our general approach, a more detailed discussion of its adaptation to peptides is given. The method is then applied to the design of peptide-based inhibitors to HIV-1 protease and the design of structural mimics of the surface region of lysozyme. The results are encouraging and point the way towards further development of interaction site-based approaches for peptide design.

Novel algorithms for searching conformational space

SummaryThe modelling of biological molecules by molecular dynamics is beset by a range of problems. The most important of these is the multiple-minima problem. The deep metastable minima can cause difficulties in proper equilibration of a molecular system and result in the simulated system being trapped in a long-lived metastable state. One way to overcome these problems is to re-engineer the ‘Newtonian Rules’ in order to more efficiently search conformational space. Re-engineering of the ‘Newtonian Rules’ implies a redesign of the physical laws arising from them. This is done in various ways by the RUSH, Hybrid Monte Carlo and PEACS algorithms. This paper explores applications of these algorithms, and compares them to a traditional molecular dynamics method.

A study of parallel molecular dynamics algorithms for N-body simulations on a transputer system

Abstract A range of algorithms are explored for performing N -body molecular dynamics simulations on a system of transputers in a ring configuration. The performances of these algorithms are investigated as a function of the size of the molecular dynamics simulations. The results obtained emphasize the importance of efficient load-balancing, and several novel methods of achieving this are described.

Ligand: A new automated system for de novo drug design

A computational approach for molecular design has been developed that provides a unified framework for the de novo generation of diverse molecules which are either similar or complementary to a specified target. This paper gives an overall view of the capabilities of the LIGAND system and goes on to illustrate them with some applications.