The design of phenylglycine containing benzamidine carboxamides as potent and selective inhibitors of factor Xa.

Factor Xa, a critical serine protease in the blood coagulation cascade, has become a target for inhibition as a strategy for the invention of novel anti-thrombotic agents. Here we describe the development of phenylglycine containing benzamidine carboxamides as novel, potent and selective inhibitors of factor Xa.

New approach to molecular docking and its application to virtual screening of chemical databases

This paper describes the validation of a molecular docking method and its application to virtual database screening. The code flexibly docks ligand molecules into rigid receptor structures using a tabu search methodology driven by an empirically derived function for estimating the binding affinity of a protein-ligand complex. The docking method has been tested on 70 ligand-receptor complexes for which the experimental binding affinity and binding geometry are known. The lowest energy geometry produced by the docking protocol is within 2.0 A root mean square of the experimental binding mode for 79% of the complexes. The method has been applied to the problem of virtual database screening to identify known ligands for thrombin, factor Xa, and the estrogen receptor. A database of 10,000 randomly chosen "druglike" molecules has been docked into the three receptor structures. In each case known receptor ligands were included in the study. The results showed good separation between the predicted binding affinities of the known ligand set and the database subset.

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 prioritized 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. 4. Application to the design of peptides.

In 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 disadvantages 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.

PRO-LIGAND: an approach to de novo molecular design. 3. A genetic algorithm for structure refinement.

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.

PRO-LIGAND: an approach to de novo molecular design. 1. Application to the design of organic molecules.

An 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-LIGAND's 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.

PRO_LIGAND: an approach to de novo molecular design. 2. Design of novel molecules from molecular field analysis (MFA) models and pharmacophores.

A computational approach for molecular design, PRO_LIGAND, has been developed within the PROMETHEUS molecular design and simulation system in order to provide a unified framework for the de novo generation of diverse molecules which are either similar or complementary to a specified target. In this instance, the target is a pharmacophore derived from a series of active structures either by a novel interpretation of molecular field analysis data or by a pharmacophore-mapping procedure based on clique detection. After a brief introduction to PRO_LIGAND, a detailed description is given of the two pharmacophore generation procedures and their abilities are demonstrated by the elucidation of pharmacophores for steroid binding and ACE inhibition, respectively. As a further indication of its efficacy in aiding the rational drug design process, PRO_LIGAND is then employed to build novel organic molecules to satisfy the physicochemical constraints implied by the pharmacophores.