CADD methods

Wermuth, C. G., The impact of QSAR and CADD methods in drug design. In Rational Approaches to Drug Design, Hoeltje, H.D., Sippl, W. (eds.). Prous Science, Barcelona, 2001, pp. 3-20. 

The choice of CADD methods that may be applied to drug design depends highly on the availability of the receptor information. If the receptor structure has been characterized by either high-resolution x-ray crystallography or NMR... 

Figure 28-26 Saquinavir (Fortovase, Invjrase), 15, was th first HIV-1 protease inhibitor designed with structure-based CADD methods to receive FDA approval. Mere saquinavir is shown inside the binding cavity of HIV-1.

CADD methods, besides determining molecular properties, can be used to suggest hypotheses. As with other scientific hypotheses, regardless of source, they must be tested experimentally. 

The progress with CADD methods has secured them a place in the repertoire of modern drug discovery research and is giving users a competitive advantage in the quest for therapeutic advances. 

Importantly, the choice of CADD methods which may be applicable directly to drug design exclusively depends upon the availability of actual viable receptor information(s). In fact, the structure-based drug design proves to be of great help provided the ensuing receptor structure has been carefully and meticulously characterized by either high-resolution NMR-spectroscopy or X-ray... 

CADD-Methods Computer-aided drug design methods. 

CADD METHODS COMPARISON FOR DETERMINING RELATIVE BINDING AFFINITES OF COX-2 INHIBITORS ... 

The recent developments of COX-2 specific NSAIDs has remarkably reduced and almost eliminated the plethora of side effects intimately associated with the traditional NSAIDs. In fact, several natural products have been duly isolated, purified, and identified as precisely selective COX-2 inhibitors. Now, with the availability of COX-2 based NSAIDs in the market, it has become rather important to strike a bonafide comparison of CADD methods for determining the relative binding affinities of COX-2 inhibitors. 

Exaplain Computer Aided Drug Design (CADD) methods vis-a-vis determining the relative binding affinities of COX-2 inhibitors. 

There are numerous coupled atomistic-continuum modeling strategies, for example, peridynamics, a family of quasi-continuum (QC) methods, finite element adaptive techniques (FEAt), coupling-of-length scales (CLS) method, and coupled atomistic-and-discrete-dislocalion (CADD) method. The grand challenge of multiscale modeling is to connect atomic-scale processes to mesoscale and bulk continuum models. 

Coupled Atomistic and Discrete Dislocation Method The coupled atomistic and discrete dislocation (CADD) method was developed by Shilkrot, Miller, Dewalt, and Curtin as a continuum/ atomistic hybrid methodology where defects (specifically dislocations) are allowed to move, can exist in both the atomistic and the continuum region, and, lastly, are permitted to cross the boundary between such domains. The methodology has later been expanded to model finite temperature as well. Similarly to the FEAt and CLS methods, CADD is based on a spatial separation of the physical problem into regions, which are modeled by either... 

In its current implementation, the CADD method can only deal with 2D problems, i.e., problems where the dislocations all have a line direction perpendicular to the modeled plane. However, the method does not contain any limitation on the dislocation character (edge, screw, or mixed) because periodic boundary conditions along the z direction are used in the atomistic region and three degrees of freedom (displacements U , Uy, and u ) are considered in the two-dimensional (x-y) continuum region. The extension of the methodology to the 3D case is not trivial and is currently being explored. 

The general boundary value problem that the CADD method wishes to solve is the following A body, containing N continuum dislocations, is divided into an atomistic region Ha and a continuum region Dc- Such a system is subject to a known traction T = Tq and initial displacements u = uq. The... 

Figure 5 Schematic representation of the continuum/atomistic coupling in the CADD method. In (a) the system is portrayed The atomic region Q,a and the continuum one fie are joined at an interface 00/ defined by a line of atoms (not necessarily straight) and are subject to a prescribed traction, To, and initial displacements, uq. In (b) the continuum/ atomistic interface is displayed in detail Solid circles represent real atoms in the bulk, gray circles represent real atoms on the interface, and unfilled circles represent pad atoms. Pad atoms are situated in the continuum region. The finite-element mapping is shown in the continuum region as well.

Applications The CADD method has been successfully applied to the investigation of Brinell nanoindentation to large penetration depth (up to 60A) in hexagonal (2D) aluminum and to the study of edge dislocation pile-ups interacting with a grain boundary in Al, under different loading conditions. ... 

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