Our group undertakes research in several major areas, which are summarized below. A bidirectional information flow between experiments and simulations is central to our research program: experimental data serves to complement the hypotheses tested by our simulations, and the high-resolution predictions from our simulations provide new hypotheses to test in the laboratory.
Heart failure drug discovery
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Despite substantial advances in the clinical management of heart failure (HF), the diagnosis continues to carry a grave prognosis, with an overall 5-year mortality rate of approximately 50%. A key molecular dysfunction in HF involves insufficient calcium transport needed to relax muscle cells in each heart beat (diastole), usually associated with impaired activity of SERCA. In our group, we use complementary computational methods, and in vitro/in vivo experiments to discover and develop novel molecules that reactivate SERCA in the failing heart. This complementary approach offers a new way to increase screening precision, to shorten the timeline to discover hit molecules, and to decrease the costs involved with HF drug development.
Design of small-molecule therapies for muscular dystrophy
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Duchenne muscular dystrophy (DMD), the most common childhood, severe form of muscular dystrophy is an X-linked disease caused by deficiency of dystrophin protein in muscle. The progressive nature of this disease leads to cardio-respiratory failure, and early death. A key abnormality in patients and animal models with DMD is the atypical intracellular calcium overload, which leads to changes in calcium handling, alterations in the excitation-contraction coupling of the myocyte, mitochondrial swelling, rupture, and ultimately myofiber necrosis. Our group addresses this problem by developing small molecules that activate calcium transport and relieve calcium overload as an innovative pharmacological therapy to ameliorate muscle pathology in DMD patients.
Development of in silico drug design methodologies
Hit-to-lead optimization is a challenging and often resource-intensive phase of lead discovery, so the early and less costly elimination of undesirable or intractable lead classes is of significant value before extensive medicinal chemistry efforts are initiated. We develop computational approach that predicts and maps favorable and unfavorable chemical fragments around a validated hit molecule for the accurate design of lead molecules, thus greatly reducing the costs associated with brute-force chemical synthesis and functional tests. This computational approach integrates molecular docking and dynamics, chemical space mining tools, and data analysis models into comprehensive pattern recognition algorithms.
Mechanisms for calcium and proton transport across the sarco/endoplasmic reticulum
We are interested in studying the mechanisms for calcium and proton transport across the sarco/endoplasmic (SR) reticulum membrane. We focus on the calcium pump, a P-type ATPase that transports calcium ions and protons across the SR membrane. Our goals are to elucidate the structural aspects of SERCA-mediated ion transport across the SR membrane, and to determine the mechanisms for coupling of calcium transport from ATP hydrolysis by SERCA at physiological conditions. We use experimental data to develop initial hypotheses, which we test and modify with computer at appropriate time scales.
Regulation of calcium uptake into the sarco/endoplasmic reticulum
SR calcium uptake in cells is regulated by a family of small transmembrane proteins. These proteins include phospholamban (PLB) and sarcolipin (SLN), which bind to SERCA and regulate its activity in cardiac and skeletal muscle. We study in atomic-level detail the mechanisms for PLB- and SLN-mediated SERCA inhibition, reactivation and uncoupling. We extend these studies to include novel regulatory micropeptides, such as endoregulin and another-regulin, which inhibit the activity of SERCA isoforms that are abundant in non-muscle cells. The goal of our research is to provide a consensus mechanism for control of SERCA function, thus gleaning real mechanistic insights into SERCA regulation in the cell.