Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming.

BACKGROUND: An important prerequisite for computational structure-based drug design is prediction of the structures of ligand-protein complexes that have not yet been experimentally determined by X-ray crystallography or NMR. For this task, docking of rigid ligands is inadequate because it assumes knowledge of the conformation of the bound ligand. Docking of flexible ligands would be desirable, but requires one to search an enormous conformational space. We set out to develop a strategy for flexible docking by combining a simple model of ligand-protein interactions for molecular recognition with an evolutionary programming search technique. RESULTS: We have developed an intermolecular energy function that incorporates steric and hydrogen-bonding terms. The parameters in this function were obtained by docking in three different protein systems. The effectiveness of this method was demonstrated by conformationally flexible docking of the inhibitor AG-1343, a potential new drug against AIDS, into HIV-1 protease. For this molecule, which has nine rotatable bonds, the crystal structure was reproduced within 1.5 A root-mean-square deviation 34 times in 100 simulations, each requiring eight minutes on a Silicon Graphics R4400 workstation. The energy function correctly evaluates the crystal structure as the global energy minimum. CONCLUSIONS: We believe that a solution of the docking problem may be achieved by matching a simple model of molecular recognition with an efficient search procedure. The necessary ingredients of a molecular recognition model include only steric and hydrogen-bond interaction terms. Although these terms are not necessarily sufficient to predict binding affinity, they describe ligand-protein interactions faithfully enough to enable a docking program to predict the structure of the bound ligand. This docking strategy thus provides an important tool for the interdisciplinary field of rational drug design.

De novo design of enzyme inhibitors by Monte Carlo ligand generation.

A new computational method for the in situ generation of small molecules within the binding site of a protein is described. The method has been evaluated using two well-studied systems, dihydrofolate reductase and thymidylate synthase. The method has also been used to guide improvements to inhibitors of HIV-1 protease. One such improvement resulted in a compound selected for preclinical studies as an antiviral agent against AIDS.

The mystery of phantom pain: growing evidence for psychophysiological mechanisms.

The direct, and much of the indirect, evidence supporting the existence psychophysiological mechanisms for phantom limb pain is reviewed. Phantom pain is shown to be a symptom class composed of different, but similarly described problems, each having its own underlying mechanisms. At least some descriptive types of phantom pain probably have mainly peripheral, as opposed to only central, origins. Although much of the direct data are preliminary, burning phantom pain is probably related to decreased blood flow in the residual limb, while cramping phantom pain is mainly related to spikelike muscle spasms in the major muscles of the residual limb. Little support is provided for psychological causes for phantom pain, but the expression of phantom pain does appear to be influenced by psychological mechanisms similarly to the ways other chronic pain conditions are influenced. The importance of a careful psychophysiological assessment of patients to treatment success is discussed. Because several different mechanisms are involved, no one treatment is likely to be effective for all of the different types of phantom pain. Appropriate combinations of self-regulation strategies aimed at controlling the underlying physiological problems are likely to be effective in reducing the incidence and severity of burning and cramping types of phantom pain.

Prevalence and characteristics of chronic phantom limb pain among American veterans. Results of a trial survey.

Twelve hundred American amputees who are military veterans were surveyed by questionnaire about their amputations, pain sensitivity, demography, treatment history, stump problems, phantom sensations, and phantom pain. Over sixty percent responded and of these 85 percent reported significant amounts of phantom pain. This is in sharp contrast to both the literature and our clinical experience which indicate that although most amputees seen in a clinical setting report some occasional minor discomfort due to their phantoms, only between one half percent and five percent experience severe phantom pain. There was no relationship between reasons for amputation, use of prosthesis, pain sensitivity, age, years since amputation, or other demographic variables and presence of severity of phantom pain. Those respondents describing phantom pain usually had either momentary episodes of intense, debilitating pain, or virtually continuous discomfort varying in intensity but reaching debilitating levels occasionally. The fairly continuous pains were all similar in description to magnified versions of comfortable phantom sensations reported by other respondents. Few of the reported treatments were of any value.