Similarity searches using topological descriptors have proved extremely useful in aiding large-scale screening. We describe alternative forms of the atom pair (Carhart et al.

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A discussion of drug-receptor theory is used to show that the three-dimensional structure, or shape, of molecules is important for biological activity. The computer-assisted molecular modeling system at Merck is described, and it is shown that this system is useful for generating and storing molecular structures, determining preferred conformation, comparing molecular shapes, and computing molecular properties. Applications of the system to the study of anti-inflammatory drugs, somatostatin-like compounds, and dihydrofolate reductase inhibitors are summarized.

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This paper describes an application of the Pople CNDO/2 semiempirical molecular orbital theory to the calculation of pyramidal inversion barriers in systems containing elements from both the first and the second row of the periodic table. It has been found that use of the standard Pople-Santry-Segal parameters consistently leads to calculated barriers which are appreciably higher than experimentally measured values and that, in certain cases involving second-row substituents adjacent to either firstor second-row inverting centers, anomalous potential curves for inversion are obtained. In an attempt to remedy these shortcomings, a revised set of parameters has been developed specifically for pyramidal inversion (Table I), empirically based to give agreement between reported and calculated barriers for one or two representative compounds for each inverting center. By use of these parameters, barriers to inversion have been calculated for some 100 structures (Table II). From a comparison of the calculated and reported values, it is concluded that the present method, while not infallible, is capable of yielding surprisingly accurate values for barriers to pyramidal inversion in a wide variety of systems, and thus can be used with considerable confidence to predict barriers for as yet unexamined or experimentally inaccessible structural types. In a number of cases, recent experimental studies have confirmed predictions made by using the present method.