Toward Rational Fragment-Based Lead Design without 3D Structures

Toward Rational Fragment-Based Lead Design without 3D Structures

Fragment-based lead discovery (FBLD) has become a prime component of the armamentarium of modern drug design programs. FBLD identifies low molecular weight ligands that weakly bind to important biological targets. Three-dimensional structural information about the binding mode is provided by X-ray crystallography or NMR spectroscopy and is subsequently used to improve the lead compounds. Despit...

Ligand mapping on protein surfaces by the 3D-RISM theory: toward computational fragment-based drug design.

In line with the recent development of fragment-based drug design, a new computational method for mapping of small ligand molecules on protein surfaces is proposed. The method uses three-dimensional (3D) spatial distribution functions of the atomic sites of the ligand calculated using the molecular theory of solvation, known as the 3D reference interaction site model (3D-RISM) theory, to identi...

Fragment - based Lead Discovery

Toward a Methodology of Rational System Design

In this paper I defend the view that there are rational methodological criteria for preferring one system design1 over another and that they are substantially the same as those of the scientific method. The parallels between the notion of a rational system design and the notion of a rational scientific theory are not coincidental: they reflect a fundamental similarity between the invention of d...

Toward a Rational Reconstruction of Design Inferences

Detecting the deliberate operation of intelligent agents in the environment is an activity so natural and pervasive that we may not be inclined, prereflectively, to classify it as an inference at all. The analogy with visual perception is initially very attractive. Just as we spontaneously discriminate among physical objects without any overt sense of deliberation, so we find ourselves sorting ...