Michael D. Altman

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Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to develop the substrate-envelope hypothesis which predicts that HIV-1 protease inhibitors that fit within the overlapping consensus volume of the substrates are(More)
The JAK-STAT pathway mediates signaling by cytokines, which control survival, proliferation, and differentiation of a variety of cells. In recent years, a single point mutation (V617F) in the tyrosine kinase JAK2 was found to be present with a high incidence in myeloproliferative disorders (MPDs). This mutation led to hyperactivation of JAK2,(More)
The electrostatic interactions between biomolecules and solvent are generally difficult to model because there exist an enormous number of solvent degrees of freedom. Continuum electrostatic models provide an approximate method to analyze these interactions; these models are typically solved numerically in either differential or integral form. In this paper(More)
Charge optimization is an essential element of rational drug design; given ligand and receptor proteins, one wishes to determine the ligand charge distribution—a vector of partial atomic charges—that maximizes the favorable change in electrostatic free energy on binding. Work in biophysics has shown that this problem is convex, and that it can be solved(More)
Computational rational drug design is the application of computer simulation techniques to improve screening processes for new drugs or to design them de novo. The goal is to identify molecules that have high affinity and specificity for a target molecule. Optimizing the electrostatic binding free energy is tractable under certain assumptions as a quadratic(More)
This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition(More)
The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors(More)
There is a clinical need for HIV protease inhibitors that can evade resistance mutations. One possible approach to designing such inhibitors relies upon the crystallographic observation that the substrates of HIV protease occupy a rather constant region within the binding site. In particular, it has been hypothesized that inhibitors which lie within this(More)
Computer simulation is an important tool for improving our understanding of biomolecule electrostatics, in part to aid in drug design. However, the numerical techniques used in these simulation tools do not exploit fast solver approaches widely used in analyzing integrated circuit interconnects. In this paper we describe one popular formulation used to(More)
We present a boundary-element method (BEM) implementation for accurately solving problems in biomolecular electrostatics using the linearized Poisson-Boltzmann equation. Motivating this implementation is the desire to create a solver capable of precisely describing the geometries and topologies prevalent in continuum models of biological molecules. This(More)