title: TRPV1 antagonism by piperazinyl-aryl compounds: A Topomer-CoMFA study and its use in virtual screening for identification of novel antagonists.
abstract: Transient Receptor Potential Vanilloid, member 1 (TRPV1), is a non-selective cation channel belonging to the transient receptor potential (TRP) family of ion channels. It occurs in the peripheral and central nervous system, activated by a variety of exogenous and endogenous stimuli, thus playing a key role in transmission of pain. This has been a target for chronic pain since more than a decade and a number of antagonists that progressed into clinical trials have failed due to the unexpected side effect of core body temperature rise, thus halting progress in this field. Of late, there has been an upsurge in research on this target, with the rat TRPV1 structure being determined, many new antagonists discovered that are temperature-neutral and many new therapeutic avenues being discovered for TRPV1, including diseases of respiratory and digestive systems, skin and bladder. Towards identifying diverse compounds to decipher the role of this target in various indications, here we report a 3D-QSAR model built using the new topomer-CoMFA methodology on a series of piperazinyl-aryl TRPV1 antagonists and the use of this model, along with a pharmacophore model and the shape of one of the potent compounds of this series, to virtually screen a subset of the ZINC database to find novel and diverse hits. These can serve as starting points to develop modality-selective antagonists for chronic pain and to elucidate the critical role of TRPV1 in the various new therapeutic areas.
authors.affiliation: Department of Computational Chemistry, Jubilant Biosys Ltd. #96, Industrial Suburb, 2nd Stage, Yeshwanthpur, Bangalore 560 064, India; School of Chemical & Biotechnology, Shanmugha Arts, Science, Technology, and Research Academy (SASTRA University), Thanjavur, Tamil Nadu 613 402, India. Electronic address: Rajendra_kristam@jubilantbiosys.com.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kristam
authors.affiliation: Tripos International, A Certara Company, St. Louis, MO 63101, USA.
authors.forename: Shashidhar N
authors.initials: SN
authors.lastname: Rao
authors.affiliation: Department of Computational Chemistry, Jubilant Biosys Ltd. #96, Industrial Suburb, 2nd Stage, Yeshwanthpur, Bangalore 560 064, India.
authors.forename: Anne Sudha
authors.initials: AS
authors.lastname: D'Cruz
authors.affiliation: School of Chemical & Biotechnology, Shanmugha Arts, Science, Technology, and Research Academy (SASTRA University), Thanjavur, Tamil Nadu 613 402, India.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Mahadevan
authors.affiliation: Department of Computational Chemistry, Jubilant Biosys Ltd. #96, Industrial Suburb, 2nd Stage, Yeshwanthpur, Bangalore 560 064, India.
authors.forename: Vellarkad N
authors.initials: VN
authors.lastname: Viswanadhan
mesh_terms: D000818:Animals; D019992:Databases as Topic; D004353:Drug Evaluation, Preclinical; D008958:Models, Molecular; D010879:Piperazines / Q000032:analysis* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D010879:Piperazines; D050916:TRPV Cation Channels
keywords: 3D-QSAR; Pain; Piperazinyl-aryl; TRPV1 antagonists; Topomer-CoMFA