Structural and Functional Diversities of the Hexadecahydro‐1H‐cyclopenta[a]phenanthrene Framework, a Ubiquitous Scaffold in Steroidal Hormones

Abstract

Hexadecahydro-1H-cyclopenta[a]phenanthrene framework (HHCPF) has been considered as one of the privileged scaffolds due to its versatile presence in many biologically essential molecules. In our quest to unravel the privileged nature of this framework, we undertook a systematic analysis of target binding and Absorption, Distribution, Metabolism, Elimination, Toxicity (ADMET)/physicochemical properties of 110 drugs containing HHCPF reported in DrugBank. Effect of number and positions of double bonds in the framework and substitutions at each carbon position on the target selectivity as well as drug like properties of these drugs were studied. Fifteen different scaffolds based on the numbers and positions of double bonds in the HHCPF were identified among these drugs. The optimum number of double bonds present in the HHCPF scaffolds was observed to be one to three, and one particular positional isomer is predominant among many scaffolds with same numbers of double bonds. Docking studies reveal the role of substituents at different positions to make specific interactions with their respective targets. Based on the docking interactions, we proposed structure based e-Pharmacophore models for seven important targets of HHCPF drugs. Good correlations were observed between the substitutions carbon positions 3 and 17 of the scaffolds and ADMET properties of the HHCPF drugs. This work enables preliminary prediction of the target selectivity and ADMET properties of a new HHCPF molecule based on the scaffold, substituents and the pharmacophoric features.

Hybrid Dynamic Pharmacophore Models as Effective Tools to Identify Novel Chemotypes for Anti-TB Inhibitor Design: A Case Study With Mtb-DapB

“…In the last few decades, there has been rapid development in computational drug discovery algorithms for ab initio protein modeling, homology modeling, protein folding dynamics, molecular docking, pharmacophore modeling, virtual screening, quantitative structure activity relationship (QSAR) etc. (Kumar Srivastava et al, 2012;Kurumurthy et al, 2012;Choudhury et al, 2014Choudhury et al, , 2015Choudhury et al, , 2016aGaur et al, 2017). Several new strategies are also designed for repurposing existing drugs or discover new ones (Passi et al, 2018).…”

Hybrid dynamic pharmacophore models as effective tools to identify novel chemotypes for anti-TB inhibitor design: A case study with Mtb-DapB

“…In the last few decades, there has been rapid development in computational drug discovery algorithms for ab initio protein modeling, homology modeling, protein folding dynamics, molecular docking, pharmacophore modeling, virtual screening, quantitative structure activity relationship (QSAR) etc. (Choudhury et al, 2014) (Choudhury et al, 2015) (Choudhury et al, 2016) (Choudhury et al, 2016) (Gaur et al, 2017) (Kumar Srivastava et al, 2012) (Kurumurthy et al, 2012). Several new strategies are also designed for repurposing existing drugs or discover new ones (Passi et al, 2018).…”

Virtual Repurposing of Ursodeoxycholate and Chenodeoxycholate as Lead Candidates Against SARS-Cov2-Envelope Protein: A Molecular Dynamics Investigation

“…Ursodeoxycholate (UDC) and chenodeoxycholate (CDC) are the drugs recommended for the treatment of gallstones as they are reported to reduce cholesterol saturation of bile (Hirota, Chijiiwa et al 1992). The tetracyclic steroid nucleus has been recognized as one of the five most common unique 'privileged' molecular scaffolds, occurring in the natural product space because of its capability to bind to multiple proteins (Choudhury, Deva Priyakumar et al 2016).CDC works by dissolving cholesterol molecules in mixed micelles. Clinically, UDC is as effective as CDC despite its poor micellar solubility of cholesterol as the former is believed to solubilize cholesterol as liquid crystals (vesicles).…”