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

Summary Recently, 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.     

Electrostatic complementarity between proteins and ligands. 3. Structural basis

Summary Electrostatic potential complementarity between ligands and their receptor sites is evaluated by the superposition of the electrostatic potential, generated by the receptor, onto the ligand potential over the ligand van der Waals surface. We would like to examine which structural factors generate this pattern of superposition. Example studies suggest that in many ligand-protein pairs, there exist principal formal charges on each molecule, largely responsible for the electrostatic potential complementarity observed. Electrostatic potential complementarity depends on the relative disposition of these principal charges and the ligand van der Waals surface. Simple mathematical models were constructed to predict the complementarity solely from structural considerations. The essential conditions for electrostatic potential complementarity were elucidated. These can be used in ligand design strategies to obtain an electrostatically optimal ligand.     

Electrostatic complementarity between proteins and ligands. 2. Ligand moieties

Summary Drug design strategies consider factors governing intermolecular interactions to build up putative ligands. In many strategies, the ligand is constructed using fragments which are placed in the site sequentially. The optimization is then performed with each fragment. We would like to examine if this optimization strategy could generate ligands with optimal electrostatic interactions. The electrostatic complementarities between constituent moieties and the receptor site have been calculated. The whole-ligand complementarity does not appear to be the mathematical mean of the individual complementarities, nor have we found a simple relationship between the moiety and whole-ligand complementarities. The results demonstrate clearly that, using a simple model, it is very difficult to predict the electrostatic potential complementarity of the whole ligand from the complementarities of its constituent chemical moieties. This means that ligand design strategies must optimize the electrostatic complementarity globally, and not moiety by moiety.     

PRO_LIGAND: An approach to de novo molecular design. 6. Flexible fitting in the design of peptides

Summary This paper describes the further development of the functionality of our in-house de novo design program, PRO_LIGAND. In particular, attention is focussed on the implementation and validation of the directed tweak method for the construction of conformationally flexible molecules, such as peptides, from molecular fragments. This flexible fitting method is compared to the original method based on libraries of prestored conformations for each fragment. It is shown that the directed tweak method produces results of comparable quality, with significant time savings. By removing the need to generate a set of representative conformers for any new library fragment, the flexible fitting method increases the speed and simplicity with which new fragments can be included in a fragment library and also reduces the disk space required for library storage. A further improvement to the molecular construction process within PRO_LIGAND is the inclusion of a constrained minimisation procedure which relaxes fragments onto the design model and can be used to reject highly strained structures during the structure generation phase. This relaxation is shown to be very useful in simple test cases, but restricts diversity for more realistic examples. The advantages and disadvantages of these additions to the PRO_LIGAND methodology are illustrated by three examples: similar design to an alpha helix region of dihydrofolate reductase, complementary design to the active site of HIV-1 protease and similar design to an epitope region of lysozyme.     

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.     

Strategic approaches to drug design. I. An integrated software framework for molecular modelling

Summary An integrated molecular graphics and computational chemistry framework is described which has been designed primarily to handle small molecules of up to 300 atoms. The system provides a means of integrating software from any source into a single framework. It is split into two functional subsystems. The first subsystem, called COSMIC. runs on low-cost, serial-linked colour graphics terminals and allows the user to prepare and examine structural data and to submit them for extensive computational chemistry. Links also allow access to databases, other modelling systems and user-written modules. Much of the output from COSMIC cannot be examined with low level graphics. A second subsystem, called ASTRAL, has been developed for the high-resolution Evans & Sutherland PS300 colour graphics terminal and is designed to manipulate complex display structures. The COSMIC minimisers, geometry investigators, molecular orbital displays, electrostatic isopotential generators and various interfaces and utilities are described.     

BUILDER v.2: Improving the chemistry of a de novo design strategy

Summary Significant improvements have been made to the de novo drug design program BUILDER. The BUILDER strategy is to find molecule templates that bind tightly to hot spots in the target receptor, and then generate bridges to join these templates. In this paper, the bridging algorithm has been further developed to improve the chemical sense and diversity of the bridges, as well as the robustness of the technique. The improved algorithm is then applied to rebuild known bridges in methotrexate and HIV protease. Finally, the entire BUILDER approach is tested by rebuilding methotrexate de novo.