Biology subjects

Pidathala, S.

Publications and source records attributed to Pidathala, S..

3 recordsLinked to original sources

bioRxiv2026

Combinatorial docking and molecular generation to navigate over 100-billion molecules for prospective ligand discovery

Commercially available make-on-demand libraries now exceed 100 billion compounds, requiring over 50 years to screen on 2,000 CPU cores using conventional docking. We present two complementary approaches to address this challenge. CombiDOCK, a combinatorial docking framework, enables exhaustive screening at the 100-billion scale within 40 days. MINT-Dock, a generative framework, accelerates navigation of this space by integrating CombiDOCK with Monte Carlo Tree Search. Benchmarked on 46 diverse targets, CombiDOCK matched full-molecule docking accuracy, and MINT-Dock achieved a 4,800-fold enrichment over random selection. Compared with prior billion-scale brute-force campaigns against {sigma}2, VMAT2, and VAChT, prospective CombiDOCK screens of the 100-billion-molecule library yielded higher hit rates and more potent ligands, while MINT-Dock achieved comparable outcomes across single- and multi-target objectives with >20-fold computational cost reductions. Docking-predicted poses of the best VAChT-binding compounds were confirmed by cryo-EM structures. These methods provide exhaustive and generative paths for navigating the trillion-molecule frontier of drug discovery.

bioinformatics↗

bioRxiv2022

Structural insights into pore dynamics of human Pannexin isoforms

Pannexins are single-membrane large-pore ion channels that release ATP upon activation. Three isoforms of pannexins, 1, 2, and 3, perform diverse cellular roles, including inflammation, differentiation, neuropathic pain, and ATP release. In this study, we report the cryoEM structure of pannexin 3 at 3.9 [A] and characterize the structural differences with pannexin isoforms 1 and 2. We observe the organization of the Pannexin 3 vestibule into two distinct chambers with a wider pore radius in comparison to both PANX1 and 2 isoforms. We further report the structure of pannexin1 congenital mutant R217H in the resolution range of 3.9 [A]. The congenital mutant R217H in transmembrane helix3 (TM3), R217H induce structural changes that leads to a partially closed pore and altered ATP interaction propensities. The channel conductance of the congenital mutant displays weakened voltage sensitivity. The results showcase a complete comparison of the three pannexin isoform structures that along with the structure of Pannexin 1 congenital mutant highlight distinct structural features of pannexin isoforms and the allosteric role of distant substitutions in dictating channel behavior in Pannexin 1.

biochemistry↗

bioRxiv2020

Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters

Norepinephrine is a biogenic amine neurotransmitter that has widespread effects on cardiovascular tone, alertness and sensation of pain. As a consequence, blockers of norepinephrine uptake have served as vital tools to treat depression and chronic pain. Here, we employ a modified Drosophila melanogaster dopamine transporter as a surrogate for the human norepinephrine transporter and determine the X-ray structures of the transporter in its substrate-free and norepinephrine-bound forms. We also report structures of the transporter in complex with inhibitors of chronic pain including duloxetine, milnacipran and a synthetic opioid, tramadol. When compared to dopamine, we observe that norepinephrine binds in a different pose, in the vicinity of subsite C within the primary binding site. Our experiments reveal that this region is the binding site for chronic pain inhibitors and a determinant for norepinephrine-specific reuptake inhibition, thereby providing a paradigm for the design of specific inhibitors for catecholamine neurotransmitter transporters. HighlightsO_LIX-ray structures of the Drosophila dopamine transporter in substrate-free and norepinephrine bound forms. C_LIO_LINorepinephrine and dopamine bind in distinct conformations within the binding pocket. C_LIO_LIChronic pain inhibitors S-duloxetine, milnacipran and tramadol bind in the primary binding site and overlap with the norepinephrine-binding pose. C_LIO_LISelective norepinephrine reuptake inhibition occurs through specific interactions at the subsite C in the primary binding pocket. C_LI

biochemistry↗