PRO_LIGAND: An Approach to de Novo Molecular Design. 2. Design of Novel Molecules from Molecular Field Analysis (MFA) Models and Pharmacophores

Abstract

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.

Computer‐Aided Drug Design

“…GRID (Goodford, 1985) is the first de novo method. Then, de novo ligand design programs such as LEGEND (Nishibta and Itai, 1993), LeapFrog (http:// www.tripos.com), LigBuilder (Wang et al, 2000), SPROUT (http://www.simbiosys.ca/sprout/index.html), CONCERTS (Pearlman and Murcko, 1996), PRO-LIGAND (Waszkowycz et al, 1994), TOPAS (Schneider et al, 2000), BUILDER (Roe and Kuntz, 1995), and LUDI (http://www.accelrys.com, Böhm, 1992a,b) were developed to build up structures according to the active site of the receptor. De novo design generates functional groups in suitable forms and suitable conformations to interact with the protein surface.…”

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

“…A further paper will detail the use of PRO_LIGAND with input data derived from a series of active structures or a 3D QSAR study [38].…”

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

“…It can extract the desired active-site atoms in a receptor or can derive a pharmacophore from a set of active molecules and conformations or a Molecular Field Analysis model [25,26].…”

“…Structures are then built up, taking care to put favourable chemistries in the correct regions of space. Methods of this type use either real chemical fragments [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] or representative templates [29][30][31][32] as building blocks. Of course, even with these broad categories there is some overlap between *To whom correspondence should be addressed.…”

“…PRO_LIGAND is our in-house facility for automated molecular design [25][26][27][28]36] and forms part of the PRO-METHEUS system for molecular design and simulation. It is essentially a rule-based method and, of the other de novo design methods, is most similar to the program LUDI [13].…”