Biology subjects

Connolly, M. P.

Publications and source records attributed to Connolly, M. P..

4 recordsLinked to original sources

bioRxiv2023

Computationally Designed Carbonic Anhydrase Inhibitors Derived from Sulfonamides for Treatment of Glaucoma

Glaucoma is a known contributor to blindness in adults. This disease occurs as a result of overactivity of the carbonic anhydrase II (CAII) enzyme. Several of the commonly used sulfonamide drugs have been used to treat the symptoms of glaucoma but have been found to have low potency. To develop a more effective drug for the treatment of glaucoma, two novel CAII inhibitor drugs were designed through bioisoteric replacement and chemical intuition. This research discusses the development of these CAII inhibitor drugs from the existing glaucoma drug known as dichlorphenamide. The drugs created in this research were found to have a better docking score within the CAII binding site than that of dichlorphenamide. The drugs proposed in this paper would need to undergo further research to determine laboratory synthesis and potential clinical trialing.

pharmacology and toxicology↗

bioRxiv2019

Evaluating molecular modeling tools for thermal stability using an independently generated dataset

Engineering proteins to enhance thermal stability is a widely utilized approach for creating industrially relevant biocatalysts. Computational tools that guide these engineering efforts remain an active area of research with new data sets and develop algorithms. To aid in these efforts, we are reporting an expansion of our previously published data set of mutants for a {beta}-glucosidase to include both measures of TM and {Delta}{Delta}G, to complement the previously reported measures of T50 and kinetic constants (kcat and KM). For a set of 51 mutants, we found that T50 and TM are moderately correlated with a Pearson correlation coefficient (PCC) of 0.58, indicated the two methods capture different physical features. The performance of predicted stability using five computational tools are also evaluated on the 51 mutants dataset, none of which are found to be strong predictors of the observed changes in T50, TM, or {Delta}{Delta}G. Furthermore, the ability of the five algorithms to predict the production of isolatable soluble protein is examined, which revealed that Rosetta {Delta}{Delta}G, ELASPIC, and DeepDDG are capable of predicting if a mutant could be produced and isolated as a soluble protein. These results further highlight the need for new algorithms for predicting modest, yet important, changes in thermal stability as well as a new utility for current algorithms for prescreening designs for the production of soluble mutants.

biophysics↗

bioRxiv2019

Computationally Guided Design of Dipeptidyl Peptidase-4 Inhibitors

The Type 2 Diabetes Mellitus (T2DM) epidemic undoubtedly creates a need for the development of new pharmaceuticals. With the goal of generating new therapeutics for this disease, computational studies were conducted to design novel dipeptidyl peptidase-4 (DPP-4) inhibitors. Two candidates, generated by chemical intuition-driven design and bioisosteric replacement, were found to have better docking scores than anagliptin, a currently available diabetes medication.

pharmacology and toxicology↗

bioRxiv2018

Community structure of phototrophic co-cultures from extreme environments

Cyanobacteria are found in most illuminated environments and are key players in global carbon and nitrogen cycling. Although significant efforts have been made to advance our understanding of this important phylum, still little is known about how members of the cyanobacteria affect and respond to changes in complex biological systems. This lack of knowledge is in part due to our dependence on pure cultures when determining the metabolism and function of a microorganism. In the work presented here we took advantage of the Culture Collection of Microorganisms from Extreme Environments (CCMEE), a collection of more than 1,000 publicly available photosynthetic co-cultures now maintained at the Pacific Northwest National Laboratory. To highlight some of their scientific potential, we selected 26 of these photosynthetic co-cultures from the CCMEE for 16S rRNA gene sequencing. We assessed if samples readily available from the CCMEE could be used to generate new insights into the role of microbial communities in global and local carbon and nitrogen cycling. Results from this work support the existing notion that culture depositories in general hold the potential to advance fundamental and applied research. If collections of co-cultures can be used to infer roles of the individual organisms remains to be seen and requires further investigation.

microbiology↗